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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome enc..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome enc..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="horizontal genetic transfer,tunneling nanotubes,Mitochondrial Diseases,extracellular vesicles,Inflammation,DAMPs,Exosomes,Communication"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00107/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="4"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Cell and Developmental Biology"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Cell Dev. Biol."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="2296-634X"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fcell.2016.00107"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="223255"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="horizontal genetic transfer; tunneling nanotubes; Mitochondrial Diseases; extracellular vesicles; Inflammation; DAMPs; Exosomes; Communication"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome encoding selected subunits of the oxidative phosphorylation complexes. Recent findings reveal that, in addition to being maternally inherited, mitochondria can traverse cell boundaries and thus be horizontally transferred between cells. Although, the physiological relevance of this phenomenon is still under debate, mitochondria uptake rescues mitochondrial respiration defects in recipient cells and regulates signaling, proliferation or chemotherapy resistance <italic>in vitro</italic> and <italic>in vivo</italic>. In this review, we outline the pathophysiological consequences of horizontal mitochondrial transfer and offer a perspective on the cellular and molecular mechanisms mediating their intercellular transmission, including tunneling nanotubes, extracellular vesicles, cellular fusion, and GAP junctions. The physiological relevance of mitochondrial transfer and the potential therapeutic application of this exchange for treating mitochondrial-related diseases are discussed.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00107/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2016/09/14"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2016/09/28"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Torralba, Daniel"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares, Madrid, Spain"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Baixauli, Francesc"><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares, Madrid, Spain"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="S谩nchez-Madrid, Francisco"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares, Madrid, Spain"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fcell.2016.00107"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00107/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":1.720169,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"cdf06e4c49803136"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! 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href="https://loop.frontiersin.org/people/112503/overview" data-event="editorInfo-a-jenniferLStow" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/112503/32" alt="Jennifer L Stow" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> Jennifer L Stow </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> The University of Queensland, Australia </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/36506/overview" data-event="editorInfo-a-hilaryAnnColler" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/36506/32" alt="Hilary Ann Coller" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> Hilary Ann Coller </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> University of California, Los Angeles, United States </div></div></a><a href="https://loop.frontiersin.org/people/163095/overview" data-event="editorInfo-a-jamesAlanMarrs" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/163095/32" alt="James Alan Marrs" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> James Alan Marrs </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> Indiana University, Purdue University Indianapolis, United States </div></div></a><a href="https://loop.frontiersin.org/people/369318/overview" data-event="editorInfo-a-rajeshGhai" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/369318/32" alt="Rajesh Ghai" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name"> Rajesh Ghai </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation"> The University of Queensland, Australia </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"> <li><a href="#h1">Abstract</a></li> <li><a href="#h2">Introduction</a></li> <li><a href="#h3">Intercellular Mitochondrial Transfer</a></li> <li><a href="#h4">Cellular Structures Mediating Intercellular Mitochondrial Transfer</a></li> <li><a href="#h5">Future Perspectives and Therapeutic Opportunities</a></li> <li><a href="#h6">Author Contributions</a></li> <li><a href="#h7">Conflict of Interest Statement</a></li> <li><a href="#h8">Acknowledgments</a></li> <li><a href="#h9">References</a></li> </ul> </div></div>  <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--typeOutline ActionsDropDown__button--iconQuote"><span class="ActionsDropDown__button__label">Export citation</span></button> <div class="ActionsDropDown__menuWrapper"> <ul class="ActionsDropDown__menu"><li><a href="/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00107/endNote" target="_blank" rel="noopener noreferrer" data-event="actionsDropDown-a-endNote" class="ActionsDropDown__option"> EndNote </a></li><li><a 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Cell Dev. Biol.</span><span>, 28 September 2016</span></div> <div class="ArticleLayoutHeader__info__journalDate"> Sec. Membrane Traffic and Organelle Dynamics </div> <div class="ArticleLayoutHeader__info__doiVolume"><span> Volume 4 - 2016 | </span> <a href="https://doi.org/10.3389/fcell.2016.00107" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fcell.2016.00107 </a></div> </div>  <div class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">Extracellular microvesicles in immune cell communication</span> <span class="Link__wrapper"><a aria-label="View all 10 articles" href="https://www.frontiersin.org/research-topics/4462/extracellular-microvesicles-in-immune-cell-communication/articles" target="_self" data-event="customLink-link-a_viewAll10Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 10 articles</span></a></span></div></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"> <a id="h1" name="h1"></a> <div class="authors"><span class="author-wrapper"> <a href="https://loop.frontiersin.org/people/374612" class="user-id-374612"><img class="pr5" src="https://loop.frontiersin.org/images/profile/374612/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="\r\nDaniel Torralba,">Daniel Torralba</a><sup>1,2</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/177508" class="user-id-177508"><img class="pr5" src="https://loop.frontiersin.org/images/profile/177508/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Francesc Baixauli,&#x;">Francesc Baixauli</a><sup>1,2</sup><sup>†</sup></span><span class="author-wrapper"><a href="https://loop.frontiersin.org/people/17933" class="user-id-17933"><img class="pr5" src="https://loop.frontiersin.org/images/profile/17933/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Francisco Snchez-Madrid,*&#x;">Francisco Sánchez-Madrid</a><sup>1,2</sup><sup>*</sup><sup>†</sup></span></div> <ul class="notes"> <li><span><sup>1</sup></span>Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares, Madrid, Spain</li> <li><span><sup>2</sup></span>Servicio de Inmunología, Instituto Investigación Sanitaria Princesa, Universidad Autonoma de Madrid, Madrid, Spain</li> </ul> <p>Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome encoding selected subunits of the oxidative phosphorylation complexes. Recent findings reveal that, in addition to being maternally inherited, mitochondria can traverse cell boundaries and thus be horizontally transferred between cells. Although, the physiological relevance of this phenomenon is still under debate, mitochondria uptake rescues mitochondrial respiration defects in recipient cells and regulates signaling, proliferation or chemotherapy resistance <i>in vitro</i> and <i>in vivo</i>. In this review, we outline the pathophysiological consequences of horizontal mitochondrial transfer and offer a perspective on the cellular and molecular mechanisms mediating their intercellular transmission, including tunneling nanotubes, extracellular vesicles, cellular fusion, and GAP junctions. The physiological relevance of mitochondrial transfer and the potential therapeutic application of this exchange for treating mitochondrial-related diseases are discussed.</p> <div class="clear"></div></div> <div class="JournalFullText"> <a id="h2" name="h2"></a><h2>Introduction</h2> <p class="mb15">Mitochondria regulate cellular homeostasis by controlling energy production, calcium signaling, cell metabolism and apoptosis. According to the endosymbiotic theory, mitochondria are derived from eubacteria that engaged in a symbiotic relationship with primitive host cells. They have maintained some of their ancestral bacterial characteristics, such as a double membrane, a proteome similar to the α-proteobacteria, and the ability to generate the majority of ATP from cells in the process of aerobic respiration or oxidative phosphorylation (OXPHOS) (<a href="#B24">Friedman and Nunnari, 2014</a>).</p> <p class="mb15">Mitochondria are endowed with their own circular genome, which is 16.6 kb in length in mammalian cells. This mitochondrial DNA (mtDNA) encodes 13 subunits that are essential components of the electron transport chain, and a translational system made of two ribosomal RNAs and 22 tRNAs, required for the translation of these proteins (<a href="#B31">Gustafsson et al., 2016</a>). During evolution, most of the mitochondrial ancestor genes have been progressively transferred to the nuclear genome, or lost; while mitochondria have acquired new components and functions from the host cell (<a href="#B42">Keeling and Palmer, 2008</a>). A typical mammalian cell contains thousands of copies of the mitochondrial genome, which are organized in mtDNA-protein complexes known as nucleoids (<a href="#B45">Kukat et al., 2015</a>). The mitochondrial genome copies of a given cell can be identical (homoplasmy), or contain more variants (heteroplasmy). Although it was generally assumed that healthy individuals exhibit homoplasmy for a single mtDNA genotype, next-generation sequencing has revealed the presence of low-level heteroplasmy in most tissues from healthy individuals (<a href="#B35">He et al., 2010</a>; <a href="#B66">Payne et al., 2013</a>). The source of this heteroplasmy is likely to be maternally inherited, as some of the low-frequency alleles found in an individual can also be found in the mother. They may also stem from somatic mutations that occur during tissue development and aging. In inherited mitochondrial DNA diseases, individuals are typically heteroplasmic and harbor both wild-type and pathogenic mtDNA molecules. Although, cells can tolerate a heavy load of pathogenic mutations, these will lead to disease when the mutation load surpasses a tolerable threshold, causing multisystemic diseases that specially affect organs with high energy requirements such as the brain, muscle, and heart. Additionally, many somatic mutations in mtDNA are related to a number of other pathologies such as cancer, cardiovascular diseases and neurodegenerative disorders, as well as the normal aging process (<a href="#B91">Wallace, 2013</a>).</p> <p class="mb15">In mammals, mitochondria are transmitted to subsequent generations exclusively through the maternal lineage. Uniparental germline inheritance reduces the benefits of recombination arising from sexual reproduction, also facilitating the appearance of maternally inherited disorders when a significant amount of mtDNA mutations are transmitted to the offspring. To counteract this, the mtDNA population undergoes a restricted process of purifying selection during oogenesis, allowing only a small population of mtDNA molecules to be amplified and transmitted. Moreover, selective replication and degradation can expand a subpopulation of mtDNA molecules at the expense of others, leading to the rapid segregation of mtDNA variants within a few generations (<a href="#B81">Stewart and Larsson, 2014</a>). During somatic cell proliferation, symmetric cell division implies that mitochondria and mtDNA are distributed between both daughter cells. Segregation of mitochondria and mtDNA involves mitochondrial fission, facilitated by the interaction of mitochondria with cytoskeletal and endoplasmic reticulum elements (<a href="#B23">Friedman et al., 2011</a>; <a href="#B47">Lewis et al., 2016</a>). Mitochondrial partitioning during symmetric division can be envisioned as a stochastic process in which mitochondrial subunits are distributed randomly between daughter cells. Conversely, recent findings suggest that asymmetric cell division differentially segregates young and old mitochondria, revealing the existence of active mechanisms that guide mitochondria partitioning between daughter cells (<a href="#B41">Katajisto et al., 2015</a>).</p> <p class="mb15">Several mechanisms maintain the integrity of mitochondria and mitochondrial genome in post-mitotic cells. Constant cycles of fusion and fission promote the intermixing and the homogenization of mitochondrial proteins, lipids and DNA between discrete organelles within the same cell (<a href="#B54">Mishra and Chan, 2014</a>). Consistent with this, cells lacking proteins involved in mitochondrial dynamics, e.g., mitofusins, show a striking heterogeneity among mitochondria in terms of protein and mtDNA nucleoid content, and membrane potential (<a href="#B12">Chen et al., 2010</a>). This causes defects in the respiratory chain function and promotes the accumulation of mtDNA mutations. The selective elimination of mitochondria through mitophagy eliminates deleterious mitochondrial mutations in heteroplasmic cells, restoring ATP levels and mitochondrial functions (<a href="#B82">Suen et al., 2010</a>; <a href="#B17">Dai et al., 2014</a>; <a href="#B87">Valenci et al., 2015</a>). However, increased mitochondrial biogenesis in heteroplasmic cells replenishes the amount of deleterious mtDNA (<a href="#B27">Gitschlag et al., 2016</a>; <a href="#B49">Lin et al., 2016</a>). Therefore, specific mechanisms regulate the stability and transmission of mitochondria and their genome during germline transmission and somatic cell proliferation. This is enabled by purifying selection and selective replication or degradation of mtDNA. In non-dividing cells, the dynamics of mitochondrial networks and their selective degradation or biogenesis maintains a healthy mitochondria repertoire.</p> <p class="mb15">Mitochondria have been recently shown to be horizontally transferred between mammalian cells, challenging current concepts of mitochondria and mtDNA segregation and inheritance. This transfer promotes the incorporation of mitochondria into the endogenous mitochondrial network of recipient cells, contributing to changes in the bioenergetic profile and in other functional properties of recipient cells, not only <i>in vitro</i> but also <i>in vivo</i>. Moreover, intercellular transfer of mitochondria involves the horizontal transfer of mitochondrial genes, which has important implications in the physiopathology of mitochondrial dysfunction. The intercellular transfer of mitochondria or their components, may also result in the initiation of stem cell differentiation, reprogramming of differentiated cells, or activation of inflammatory signaling pathways. Diverse structures mediate intercellular mitochondrial transfer. These include tunneling nanotubes (TNTs), microvesicles, mitochondrial ejection or cytoplasmic fusion, among others. Future research in this field is likely to open new avenues for the treatment of mitochondrial related disorders, e.g., transfer of healthy, or genetically corrected, mitochondria.</p> <p class="mb0">In this review, we discuss the relevance of mitochondrial transfer in physiological processes. Starting from an integrated view of the molecular mechanisms mediating intercellular mitochondrial transmission, we delve into the pathophysiological consequences of horizontal mitochondrial transfer. Finally, we discuss how intercellular mitochondrial transfer can be exploited as a new avenue for the treatment of mitochondrial-related diseases.</p> <a id="h3" name="h3"></a><h2>Intercellular Mitochondrial Transfer</h2> <p class="mb15">The existence of nanotubular structures mediating the transfer of many cellular constituents (<a href="#B76">Rustom et al., 2004</a>) has demonstrated the widespread ability of mammalian cells to donate or receive organelles from other cells (<a href="#B26">Gerdes et al., 2007</a>; <a href="#B20">Davis and Sowinski, 2008</a>). Such transfer involves many different cell types <i>in vitro</i> and <i>in vivo</i>, including lymphocytes, neurons or cardiomyocytes. Organelle exchange represents a special form of intercellular communication that allows unidirectional or bidirectional transfer, not only of signals, small molecules or ions, but also of defined intracellular structures such as mitochondria, lysosomes, endosomal vesicles and plasma membrane components (<a href="#B75">Rogers and Bhattacharya, 2013</a>).</p> <p class="mb15">The first evidence of functional mitochondrial transfer involved healthy mitochondria from human stem cells rescuing mitochondrial respiration in mitochondria-depleted recipient cells (<a href="#B79">Spees et al., 2006</a>). Cells devoid of intrinsic mitochondrial function by mtDNA depletion through long-term ethidium bromide treatment, do not survive in standard media. However, when these cells were co-cultured with mesenchymal stem cells (MSCs) or fibroblasts that donated functional mitochondria, they acquired mitochondria and re-established aerobic respiration. The careful examination of mitochondrial and nuclear DNA polymorphisms in the rescued clones excluded cell fusion as the main mechanism of mitochondrial transfer, also confirming the stem cell origin of the transferred mtDNA (<a href="#B79">Spees et al., 2006</a>). Transfer did not occur through the passive uptake of mitochondrial fragments or isolated organelles, but rather involved active processes such as the formation of TNTs and/or the vesicular transfer of mtDNA or mitochondrial fragments.</p> <p class="mb15">Other groups have demonstrated that the horizontal cell-to-cell transfer of mitochondria and mitochondrial genome can occur among many other mammalian cells <i>in vitro</i> and <i>in vivo</i> (<a href="#B7">Berridge et al., 2016</a>). Mitochondrial transfer supports the exogenous replacement of damaged mitochondria, thereby rescuing mitochondrial defects (<a href="#B33">Hayakawa et al., 2016</a>; <a href="#B65">Patananan et al., 2016</a>). Most studies used stem cells as mitochondrial donors, but some others also used immortalized cells or primary cells from the same or different species (<a href="#B7">Berridge et al., 2016</a>). Although, there are some concerns regarding whether intercellular mitochondrial transfer is a physiologically relevant process or it is only observed in cell culture conditions, recent evidence strongly supports that mitochondrial transfer does occur <i>in vivo</i> and may be involved in diverse pathophysiological situations, such as tissue injury and cancer progression (<a href="#B37">Islam et al., 2012</a>; <a href="#B4">Ahmad et al., 2014</a>; <a href="#B84">Tan et al., 2015</a>; <a href="#B33">Hayakawa et al., 2016</a>; <a href="#B57">Moschoi et al., 2016</a>).</p> <p class="mb15">Intercellular mitochondrial transfer rescues injured cells from mitochondrial dysfunctions related with several models of cell survival associated to stress responses. MSC improve survival and restore cell damage by transferring their mitochondria through TNTs to EC or cardiomyocytes previously subjected to an <i>in vitro</i> model of ischemia-reperfusion, in which cells are cultured under glucose-oxygen deprivation and then reoxygenated (<a href="#B50">Liu et al., 2014</a>; <a href="#B32">Han et al., 2016</a>). Similarly, the transfer of mitochondria from MSC to human umbilical vein endothelial cells (HUVEC) previously subjected to <i>in vitro</i> ischemia-reperfusion, restores aerobic respiration in EC independently of cellular trans-differentiation or the release of paracrine factors. Notably, aerobic restoration is not reestablished in HUVEC when these are cultured alone or with MSCs containing dysfunctional mitochondria promoted by mtDNA depletion (<a href="#B50">Liu et al., 2014</a>). Interestingly, phosphatidylserine exposure on injured endothelial cells acts as a “find-me” signal that triggers the emergence of tunneling nanotubes and guides them from MSC to injured HUVECs (<a href="#B50">Liu et al., 2014</a>). Mitochondrial transfer from MSCs to lung epithelium also attenuates cigarette smoke-induced lung damage (<a href="#B48">Li et al., 2014</a>), while transfer between MSC and innate immune cells via TNTs and microvesicle secretion enhances the capacity of alveolar macrophages to engulf invading bacteria in an <i>E.coli</i> pneumonia model (<a href="#B38">Jackson et al., 2016</a>). Based on these results, it has been proposed that cell stress is required for organelle transfer. Mitochondrial transfer is triggered by an almost complete absence of mitochondrial function, such as mtDNA depletion or treatment with mitochondrial inhibitors, since transfer is not detected to cells harboring pathogenic mutations that partially affect mitochondrial function (<a href="#B13">Cho et al., 2012</a>; <a href="#B92">Wang and Gerdes, 2015</a>). An intriguing question pertains to the degree of cellular damage required to initiate intercellular transfer of functional mitochondria. We also ponder about the mechanisms by which the healthy cell detects the degree of metabolic shutdown of the stressed cell and makes a “judgment call” to restore the functionality of the stressed cell, instead of permitting apoptosis to remove the damaged cell. This would be of particular interest in non-replaceable cell lineages such as adult neurons. Accordingly, the transfer of mitochondria from astrocytes to neurons has a neuroprotective effect after stroke (<a href="#B33">Hayakawa et al., 2016</a>).</p> <p class="mb0">Mitochondrial transfer seems to be involved in stem cell-triggered repair of damaged cells (<a href="#B71">Plotnikov et al., 2008</a>). Mitochondrial transfer from stem cells to lung epithelial cells and endothelial cells is an important mechanism by which MSC exert their protective effects in several animal models of lung diseases. A seminal study demonstrated that transfer of intact mitochondria can contribute to tissue repair <i>in vivo</i> (<a href="#B37">Islam et al., 2012</a>). In that study, bone marrow-derived stem cells (BMSCs) infused to the trachea of lipopolysaccharides (LPS)-treated mice attached to injured alveolar epithelial cells by a mechanism involving connexins (Figure <a href="#F1">1</a>). Connexin oligomerization forms channels or GAP junctions that connect two cells, allowing the transfer of only small metabolites, ions or small RNAs. Connexins, and specifically connexin-43, regulate intercellular mitochondrial transfer by promoting the attachment of BMSCs to LPS-injured alveolar epithelial cells, leading to the formation of nanotubes and microvesicles that mediate mitochondrial transfer. Mitochondria acquisition by the alveolar cells triggered the restoration of ATP levels and increased the secretion of pulmonary surfactant. Silencing of RISP, a subunit of the mitochondrial complex III, in BMSCs reduced their capacity to restore ATP levels in recipient alveolar epithelial cells, avoiding protection from LPS-injury (<a href="#B37">Islam et al., 2012</a>). These results implicated mitochondrial transfer as a driver of the <i>in vivo</i> benefits of mesenchymal stem cell therapy in models of acute lung injury and other inflammatory diseases, enhancing cellular bioenergetics and improving organ function. A follow-up study in mice provided a molecular mechanism to potentially increase the therapeutic efficiency of MSC by modulating the extent of mitochondrial transfer (<a href="#B4">Ahmad et al., 2014</a>). This study described that the levels of Miro1, a protein connecting mitochondria to cytoskeletal motor proteins, regulate the efficiency of intercellular movement of mitochondria. Hence, overexpression of Miro1 in MSC increased mitochondrial transfer from stem cells into stressed epithelial cells via intercellular TNTs, attenuating epithelial cell apoptosis and reducing inflammatory cell infiltration, collagen deposition and mucus hypersecretion in the lungs. Overall, Miro1 overexpression improves the therapeutic efficiency of mitochondrial transfer across multiple models of asthma <i>in vivo</i> and <i>in vitro</i> (<a href="#B4">Ahmad et al., 2014</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" name="figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a> <p><strong>Figure 1. Cellular mechanisms of intercellular mitochondrial transfer. (A)</strong> <i>Tunneling nanotubes</i> (TNT) are long ultrathin structures with diameters ranging from 50 to 200 nm and a length that allow organelle transfer between two spatially separated cells. TNTs contain cytoskeletal elements such as actin and microtubules depending on the cell type. Myosin is a fundamental protein for the organelle transfer, a process where high rates of ATP consumption are needed. Rho GTPases play an important role in organelle transfer through TNT. Miro1 and microtubules have been involved in the transfer of mitochondria upon injury (<a style="color:grey;" href="#B4">Ahmad et al., 2014</a>). <strong>(B)</strong> <i>Cell fusion</i> is a process, in which two independent cells fuse their membranes and share organelles and cytosolic compounds, however nuclei remain intact. Cell fusion can be transitory and therefore lose their integrity transiently or complete, where cells will share cytoplasm continuously, for example in muscle cells. It has been shown that after myocardial infarct stem cell therapy can lead to a better recovery and it is proved that partial or total fusion events can happen between cardiomyocytes and stem cells (<a style="color:grey;" href="#B61">Oh et al., 2003</a>). By this mechanism mitochondrial respiration can be restored and this could be an indicative marker for cardiac regeneration after infarct. <strong>(C)</strong> <i>GAP junctions</i>. LPS treatment increases connexin 43 expression in alveolar cells. Connexins facilitate the attachment of BMSC to the alveolar epithelial cells, and produce vesicles and nanotubes to share mitochondria with the damaged cells protecting against acute lung injury (<a style="color:grey;" href="#B37">Islam et al., 2012</a>).</p></div> <div class="clear"></div> <div class="DottedLine"></div> <p class="mb0 w100pc float_left mt15">Cancer cells opportunistically acquire mitochondria to optimize or repair their metabolic machinery. In this regard, horizontal transfer of mtDNA from host cells to tumor cells with compromised respiratory function has been described (<a href="#B84">Tan et al., 2015</a>). Tumor cells devoid of mtDNA, a model of extreme mtDNA damage, acquire mtDNA from surrounding donor healthy cells, repairing the transcriptional and translational activity of mtDNA-encoded genes and triggering a substantial recovery of mitochondrial respiration, as well as tumor initiation efficacy and metastasis capacity. A major source of healthy mitochondria in these contexts are stromal cells, which can modulate the phenotype of the tumor by direct mitochondria transfer. Cancer cells and stromal cells communicate through TNTs, and mitochondrial transfer via TNTs from endothelial to cancer cells enhances their chemoresistance to doxorubicin <i>in vitro</i> (<a href="#B64">Pasquier et al., 2013</a>). In addition, mitochondrial transfer from bone marrow mesenchymal cells to acute myelogenous leukemia cells <i>in vivo</i> confers chemoresistance and survival advantage (<a href="#B57">Moschoi et al., 2016</a>). These findings highlight the requirement of mitochondrial respiration for tumorigenesis and metastasis, and support mitochondrial transfer as a mechanism for the efficient metabolic adaptation of tumor cells to hostile microenvironments (<a href="#B84">Tan et al., 2015</a>).</p> <h3>Mitochondrial Transfer beyond Cell Rescue</h3> <p class="mb15">Intercellular organelle transfer participates in cell differentiation and/or de-differentiation (<a href="#B71">Plotnikov et al., 2008</a>, <a href="#B70">2010</a>). Human adipose-derived or bone marrow-derived stem cells can reprogram differentiated mouse cardiomyocytes into a progenitor-like state. This process involves partial cell fusion and mitochondrial transfer. Deprivation of mtDNA in stem cells dramatically decreased the efficiency of the reprogramming process. Although, mtDNA depletion may affect cell stemness and the ability to donate mitochondria, these results suggest that mitochondrial transfer from stem cells to adult cardiomyocytes helps their conversion to the progenitor state through metabolic reprogramming (<a href="#B2">Acquistapace et al., 2011</a>). Stem cell interaction with other cell types does not necessarily result in actual differentiation, but it may rather initiate a proliferative response, as observed during mitochondrial transfer from vascular smooth muscle cells to MSCs (<a href="#B88">Vallabhaneni et al., 2012</a>).</p> <p class="mb15">The release of mitochondria or mitochondrial components into the extracellular space has important immune consequences. After an episode of acute injury, release of mitochondrial components into the extracellular medium and bloodstream may trigger potent pro-inflammatory responses. In fact, mitochondrial components can be recognized by cells of the immune system as damage-associated molecular patterns (DAMPs) (<a href="#B99">Zhang et al., 2010</a>; <a href="#B25">Galluzzi et al., 2012</a>; <a href="#B96">West et al., 2015</a>). Different mitochondrial proteins such as TFAM, together with other mitochondrial DAMPs like N-formyl peptides, mtDNA, cardiolipin or extracellular ATP, robustly activate the inflammatory response (<a href="#B95">Weinberg et al., 2015</a>).</p> <p class="mb15">Mitochondrial DNA induces inflammation when found beyond mitochondrial membrane boundaries (<a href="#B99">Zhang et al., 2010</a>). Mitochondrial DNA injected directly into mice joints causes inflammation and arthritis (<a href="#B15">Collins et al., 2004</a>). Moreover, mitochondrial DNA that escapes autophagy leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in a cell-autonomous manner (<a href="#B62">Oka et al., 2012</a>). When abnormally found in the cytosol, mtDNA triggers NRLP3-inflammasome activation and STING-dependent antiviral signaling (<a href="#B78">Shimada et al., 2012</a>; <a href="#B96">West et al., 2015</a>), which ultimately leads to cell death. Neutrophils release to the extracellular environment oxidized mitochondrial nucleoids that activate the interferon response in pathological situations such as human systemic lupus erythematosus (<a href="#B11">Caielli et al., 2016</a>), whereas activated platelets release into the bloodstream entire mitochondria or mitochondria encapsulated in microparticles to boost the inflammatory response (<a href="#B8">Boudreau et al., 2014</a>). Interestingly, mtDNA released by eosinophils or basophils contribute to inflammatory responses creating DNA net traps to fight against invading pathogens (<a href="#B98">Yousefi et al., 2008</a>; <a href="#B56">Morshed et al., 2014</a>).</p> <p class="mb15">Mitochondria-dependent activation of the inflammatory response has important consequences to understand intercellular mitochondrial transfer. In this regard, innate immune cells target cells containing allogenic mtDNA (<a href="#B36">Ishikawa et al., 2010</a>). Such recognition mechanism, displayed by natural killer cells and dendritic cells, is not yet understood, but it is likely to control the extent of intercellular mitochondrial transfer in pathophysiological conditions. As a consequence, careful modulation of immune surveillance mechanisms in recipient cells could be a potential strategy to boost exogenous mitochondrial donation for therapeutic purposes. Consistent with this view, MSC secrete microvesicles containing depolarized mitochondria that are engulfed by macrophages in the stem cell niche (<a href="#B68">Phinney et al., 2015</a>). Together with microvesicles, MSC secrete exosomes that inhibit TLR signaling and macrophage activation, thereby promoting specific tolerance to the transferred mitochondria. Also, mitochondrial transfer by MSCs may enhance their own survival by unloading partially depolarized mitochondria into more professional phagocytic cells such as macrophages (<a href="#B68">Phinney et al., 2015</a>).</p> <p class="mb0">A similar process of transcellular degradation of transferred mitochondria (“transmitophagy”) has been observed in neurons at the optic nerve head (ONH). Axonal protrusions and evulsions within the ONH contain mitochondria that are shed from neurons and degraded by the lysosomes of neighboring astrocytes (glial cells) (<a href="#B18">Davis et al., 2014</a>). This process accounts for the majority of mitochondrial turnover, rather than mitophagy in the ganglion cell soma. The most likely reason for this mechanism is that it is energetically taxing to transport axonal mitochondria back to the soma for degradation. The system thus takes advantage of the presence of a subset of astrocytes with extreme phagocytic activity on the ONH (<a href="#B19">Davis and Marsh-Armstrong, 2014</a>). In agreement, astrocytes can phagocytose whole synapses (<a href="#B14">Chung et al., 2013</a>). A similar autophagy-assisted phagocytosis is also involved in the turnover of photoreceptor outer segments by retinal pigment epithelial cells (<a href="#B44">Kim et al., 2013</a>). Although, transmitophagy is a relatively novel process in the nervous system, similar transcellular degradation of mitochondria occurs in gametes upon fertilization, in which sperm mitochondria are actively degraded by oocytes by the same molecular machinery used in autophagy (<a href="#B5">Al Rawi et al., 2011</a>; <a href="#B77">Sato and Sato, 2011</a>).</p> <h3>Horizontal Gene Transfer</h3> <p class="mb15">Although widely observed in prokaryotes, horizontal gene transfer (HGT) is in general a rare phenomenon in metazoans. However, HGT in eukaryotes might be less rare than previously anticipated (<a href="#B16">Crisp et al., 2015</a>), and it has likely contributed to biochemical diversification during animal evolution. The horizontal transfer of genetic material between species of <i>Saccharomyces</i> has been postulated during the evolution of modern yeast species (<a href="#B53">Marinoni et al., 1999</a>). Likewise, asexual bdelloid rotifers have experienced extensive HGT from non-metazoan genes (<a href="#B28">Gladyshev et al., 2008</a>), which might have compensated the lack of genetic heterogeneity due to the absence of sexual recombination (<a href="#B22">Eyres et al., 2015</a>). One interesting example is the horizontal transfer of entire genomes via mitochondrial fusion in the angiosperm <i>Amborella</i>. Specifically, <i>Amborella</i> mtDNA includes a diverse collection of foreign sequences corresponding to about six genome equivalents of mtDNA acquired from mosses, angiosperms and green algae (<a href="#B74">Rice et al., 2013</a>).</p> <p class="mb15">One of the first evidences of <i>in vivo</i> horizontal mitochondrial gene transfer was found in a transmissible canine venereal tumor (CTVT), which is a highly adapted form of cancer that is transmitted as an allograft during mating of feral dogs. Phylogenetic evidence supports that CTVT cells periodically acquire mitochondria from their hosts to support long-term survival. Gene transfer events might rescue CTVT mitochondrial function, allowing the tumor to overcome the high mutation rate that would promote the accumulation of deleterious mutations in their own mitochondria (<a href="#B72">Rebbeck et al., 2011</a>).</p> <p class="mb0">The intercellular exchange of mtDNA for the maintenance of heteroplasmy in cells has been recently proposed (<a href="#B39">Jayaprakash et al., 2015</a>). Heteroplasmy is maintained in individual daughter cells over multiple cell divisions, which suggests the existence of active mechanisms that counteract mtDNA drift toward homoplasmy. Using a novel method to enzymatically purify mtDNA, the authors demonstrate the intercellular transfer of mtDNA between cell lines with distinct mtDNA haplotypes in co-culture experiments (<a href="#B39">Jayaprakash et al., 2015</a>), raising the intriguing possibility that horizontal mtDNA exchange may regulate heteroplasmy <i>in vivo</i>.</p> <a id="h4" name="h4"></a><h2>Cellular Structures Mediating Intercellular Mitochondrial Transfer</h2> <p class="mb0">The molecular and signaling mechanisms by which cells containing dysfunctional mitochondria acquire mitochondria from other cells, and how this process is regulated remain unclear. Cells likely possess mechanisms to trigger organelle exchange in response to injury signals emanating from the recipient cell. However, the molecular cues that initiate such crosstalk are still unidentified. Tunneling nanotubes are seen so far as the main cellular structure that mediates intercellular mitochondrial transfer. Other mechanisms have been proposed, including membrane microvesicles, cell fusion or mitochondrial ejection. Transfer through these diverse structures may result in different functional outcomes for the recipient cells, i.e., functional mitochondrial acquisition, immune activation or transmitophagy. Thus, a clear understanding on the mechanisms mediating mitochondrial transmission will shed light on how mitochondrial transfer is regulated and can be exploited for therapeutic purposes.</p> <h3>Tunneling Nanotubes</h3> <p class="mb15">Tunneling nanotubes (TNTs) form between different cell types <i>in vitro</i> and <i>in vivo</i> (Figure <a href="#F1">1</a>). Tunneling nanotubes facilitate the selective exchange of organelle or membrane vesicles and small soluble cytoplasmic and membrane molecules. The establishment of a nanotube begins with the formation of a filopodium-like membrane protrusion that retracts after reaching the receptor cell, leaving an ultrafine structure that is separated from the substrate. TNTs appear to be essential for effective mitochondrial transfer, since impairing TNT formation with chemical inhibitors or mechanical stress reduces mitochondrial exchange, whereas inhibition of phagocytosis, endocytosis or exocytosis have little or no effect (<a href="#B9">Bukoreshtliev et al., 2009</a>). Transfer of mitochondria through TNTs is usually unidirectional, from the cell that initiated the formation of TNT to the receptor cell (<a href="#B76">Rustom et al., 2004</a>; <a href="#B9">Bukoreshtliev et al., 2009</a>). However, bidirectional transfer has also been reported (<a href="#B34">He et al., 2011</a>).</p> <p class="mb15">Certain types of stress agents increase TNT formation and mitochondrial transfer. Doxorubicin treatment increases mitochondrial transfer from endothelial progenitors to mature endothelial cells challenged with doxorubicin (<a href="#B97">Yasuda et al., 2010</a>), while ethidium bromide treatment enhances mitochondrial transfer from MSC to osteosarcoma-treated cells (<a href="#B13">Cho et al., 2012</a>). Similarly, multipotent mesenchymal stem cells transfer mitochondria to lung epithelium cells treated with cigarette smoke (<a href="#B48">Li et al., 2014</a>). <i>In vivo</i>, acute lung injury promoted either by rotenone or TNF-treatment is required for the transfer of mitochondria from stem cells to lung epithelial cells (<a href="#B4">Ahmad et al., 2014</a>). In general, mitochondrial damage is the main trigger of TNT-based mitochondrial transfer (Figure <a href="#F1">1</a>).</p> <p class="mb0">Other conditions that favor TNT formation are serum starvation and hydrogen peroxide. These conditions activate p53 and nanotube formation in hippocampal astrocytes and neurons (<a href="#B94">Wang et al., 2011</a>). Similarly, hyperglycemic or acidified medium, as well as cytokines that stimulate epithelial-to-mesenchymal transition, increase mitochondrial transfer through tunneling nanotube formation (<a href="#B51">Lou et al., 2012</a>). Therefore, stress can induce TNT formation, but further research is required to understand how TNT-mediated mitochondrial transfer is regulated. Notably, the protein S100A4 and its receptor guide the direction of nanotube growth (<a href="#B83">Sun et al., 2012</a>). In stressed cells, p53 activates caspase-3 to cleave S100A4, creating a gradient in which the TNT initiating cell has the lower levels of the protein (<a href="#B83">Sun et al., 2012</a>).</p> <h3>Extracellular Vesicles</h3> <p class="mb0">Almost every cell type secretes a heterogeneous population of vesicles to the extracellular medium. This group of vesicles, ranging from 40 to 1000 nm, is referred to as extracellular vesicles (EVs). EVs can be divided into microvesicles, exosomes and apoptotic bodies, depending on their origin, size and molecular composition (Figure <a href="#F2">2</a>). EVs are vehicles of intercellular communication in a number physiological and pathological processes (<a href="#B55">Mittelbrunn and Sánchez-Madrid, 2012</a>), and can be used as biomarkers of health and disease (<a href="#B69">Pitt et al., 2016</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" name="figure2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/223255/fcell-04-00107-HTML/image_m/fcell-04-00107-g002.jpg" alt="www.frontiersin.org" id="F2" loading="lazy"> </picture> </a> <p><strong>Figure 2. Loading of mitochondrial components in Extracellular Vesicles</strong>. Exosomes are small vesicles from 50 to 150 nm with an endocytic origin. The inward budding of late endosomes or multivesicular bodies (MVB) forms intraluminal vesicles that are released into the extracellular environment as exosomes through fusion of the MVB with the plasma membrane. Microvesicles, also called ectosomes, shed directly from plasma membrane and are very heterogeneous in size and composition. Apoptotic bodies are larger than 1 μm and are released by apoptotic cells that shed parts of their cytoplasm and organelles surrounded by plasma membrane (<a style="color:grey;" href="#B55">Mittelbrunn and Sánchez-Madrid, 2012</a>). Extracellular vesicles can contain mitochondrial fragments which include mitochondrial proteins and mtDNA (depicted in yellow and orange). Bigger particles can be loaded with full functional mitochondria (<a style="color:grey;" href="#B68">Phinney et al., 2015</a>).</p></div> <div class="clear"></div> <div class="DottedLine"></div> <p class="mb15 w100pc float_left mt15">Mitochondrial components have been detected in EVs, although the mechanisms by which mitochondrial proteins and mtDNA are loaded in the diverse EVs are still unknown. Exosomes, with a size ranging 40–150 nm, contain genetic material, mostly small RNAs (<a href="#B90">Villarroya-Beltri et al., 2014</a>), but genomic and mitochondrial DNA have also been detected (<a href="#B29">Guescini et al., 2010a</a>,<a href="#B30">b</a>; <a href="#B40">Kahlert et al., 2014</a>; <a href="#B85">Thakur et al., 2014</a>). Larger EVs can contain entire mitochondrial particles and mtDNA, as observed in mesenchymal stem cells and astrocytes (<a href="#B68">Phinney et al., 2015</a>; <a href="#B33">Hayakawa et al., 2016</a>). These cells produce EVs with regenerative potential in several tissues under damaging conditions (<a href="#B43">Khan et al., 2015</a>; <a href="#B59">Nakamura et al., 2015</a>; <a href="#B63">Ong and Wu, 2015</a>). Whether mitochondrial material contained in these vesicles participates in the regenerative potential of stem cells is yet to be shown.</p> <p class="mb0">EVs participate in intercellular mitochondrial transfer (<a href="#B79">Spees et al., 2006</a>; <a href="#B37">Islam et al., 2012</a>; <a href="#B39">Jayaprakash et al., 2015</a>). Horizontal transfer of mitochondria occurs through the transfer of either mitochondria-derived vesicles or intact mitochondria. To date, the mechanisms of intercellular transfer of free mtDNA across both mitochondrial inner and outer membranes and the plasma membrane remain elusive. Also, the transfer of whole mitochondrial particles is the most likely event mediating rescue of mitochondrial function through EVs during intercellular mitochondrial transfer, in which some cells would acquire a few mitochondria and replicate their mtDNA.</p> <h3>Cell Fusion</h3> <p class="mb15">Cell fusion is a process in which two independent cells fuse their membranes and share organelles and cytosolic compounds, while their nuclei remain intact. Permanent cell fusion result in cells that share the cytoplasm and possess unique karyotypes, while partial cell fusion allows transient, but direct, intercellular communication and exchange of multiple protein complexes and even subcellular organelles, including mitochondria. Fusion is a rare event in developed eukaryotic organisms, and a strict regulation of fusogen proteins and their receptors expression ensures that it only occurs under specific conditions (<a href="#B3">Aguilar et al., 2013</a>).</p> <p class="mb15">Adult and embryonic stem cells have been reported to fuse with cardiomyocytes, hepatocytes and neurons, which might contribute to the differentiation, plasticity, or maintenance of these cell types (<a href="#B6">Alvarez-Dolado et al., 2003</a>). Injury and inflammation may drive cell fusion in target organs. Cells from the myeloid and lymphoid lineage can fuse in low rates with different tissues in response to injury or inflammation (<a href="#B60">Nygren et al., 2008</a>). Cell fusion improved regeneration in rodent livers that received bone marrow transplants (<a href="#B89">Vassilopoulos et al., 2003</a>; <a href="#B93">Wang et al., 2003</a>). Myocardial infarction also triggers fusion events between cardiomyocytes and bone marrow transplanted cells (<a href="#B61">Oh et al., 2003</a>; Figure <a href="#F1">1</a>). Similarly, human MSC may fuse to small airway epithelial cells upon insult <i>ex vivo</i> (<a href="#B80">Spees et al., 2003</a>). However, to which extent mitochondrial transfer in these scenarios participates in the potential of stem cell fusion is unknown.</p> <p class="mb0">Cell fusion can modify the potential of the cells involved, having important implications in regeneration and cancer (<a href="#B3">Aguilar et al., 2013</a>). A major concern is whether fusion is physiologically relevant, since most studies used pluripotent or multipotent stem cells as at least one of the fusion partners. It is difficult to evaluate its actual impact in tissues, since cytokinesis may occur after fusion events, leaving new synkaryons that could be hardly distinguished from the rest of the cells in the tissue. This is the underlying reason why <i>in vivo</i> reports of adult cell fusion are scarce, apart from those cells that form heterokaryons as part of their functional cycle, e.g., muscle, placenta or macrophages.</p> <h3>Other Cellular Mechanisms</h3> <p class="mb0">Mitochondrial extrusion is another possible mechanism for mitochondrial transfer. It allows the release of mitochondria or mitochondrial components from cells under specific conditions. During tumor necrosis factor α-induced cell death, cytoplasmic vacuoles engulf mitochondria, which subsequently fuse with the plasma membrane, releasing free mitochondria to the extracellular medium (<a href="#B58">Nakajima et al., 2008</a>). Likewise, LPS stimulation promotes the fusion of autophagolysosomes with the plasma membrane and the release of mitochondrial components that activate the inflammatory response (<a href="#B86">Unuma et al., 2015</a>). Neutrophils can extrude mitochondrial components, specifically oxidized mitochondrial nucleoids, which boost type I interferon secretion and can lead to the development of lupus (<a href="#B11">Caielli et al., 2016</a>). Under high rates of reactive oxygen species (ROS) HeLa cells can extrude fragments of mitochondria (<a href="#B52">Lyamzaev et al., 2008</a>). Basophils release mtDNA in ROS dependent manner to create extracellular DNA traps to fight bacteria (<a href="#B56">Morshed et al., 2014</a>). Likewise, eosinophils rapidly release mtDNA in the extracellular space to bind and kill infectious bacteria (<a href="#B98">Yousefi et al., 2008</a>). Mitochondrial extrusion not only occurs <i>in vitro</i>, but also <i>in vivo</i>. For example, platelets extrude functional mitochondria both encapsulated in microparticles and as free organelles. This way, they enhance inflammatory responses (<a href="#B8">Boudreau et al., 2014</a>). In addition, hepatocytes of mice treated with anti-Fas antibody extruded mitochondria, which were detected in the perisinusoidal space and in serum (<a href="#B58">Nakajima et al., 2008</a>).</p> <a id="h5" name="h5"></a><h2>Future Perspectives and Therapeutic Opportunities</h2> <p class="mb15">Horizontal mitochondrial transfer among cells occurs <i>in vitro</i> and <i>in vivo</i>. However, whether mitochondria move between cells under physiological conditions, and the precise role of this transfer remain unknown. Stem cells are likely organelle donors; thus, adult stem cells, mesenchymal stromal cells, fibroblasts, and hematopoietic stem cells, emerge as potential mitochondrial donors. These cells may transfer mitochondria to surrounding cells in their niche, thus affecting cell differentiation, proliferation, tissue homeostasis, development and aging. During the course of an immune response, immune cells show high capacity to exchange surface receptors and intercellular material (<a href="#B73">Rechavi et al., 2009</a>). These cells can also extrude mitochondrial components under specific conditions (<a href="#B95">Weinberg et al., 2015</a>). Regarding the control of immune responses by those mechanisms, cognate immune cell-cell interactions such as immune synapses between lymphocytes and antigen-presenting cells, lymphocyte adhesion and migration across inflamed tissues or macrophage patrolling, may represent physiological scenarios in which mitochondrial intercellular exchange could control signaling, proliferation, bioenergetics or transcellular degradation of mitochondria. Professional phagocytic cells involved in inflammation and tissue regeneration may also acquire exogenous mitochondria (<a href="#B68">Phinney et al., 2015</a>), as it has been observed in the optic nerve head (<a href="#B18">Davis et al., 2014</a>). Notably, astrocytes transfer mitochondria to neurons supporting neuronal viability after ischaemic stroke (<a href="#B33">Hayakawa et al., 2016</a>). Whether neurons and microglia crosstalk through intercellular mitochondrial transfer should be further addressed, in order to determine if defects on this type of communication are involved in pathogenesis and can represent a therapeutic target.</p> <p class="mb15">Unraveling the physiological significance of mitochondrial transfer requires the development of novel fluorescence and genetic mitochondrial tracking tools. Many of the studies referred here use fluorescent dyes to track mitochondrial transfer, but the possibility of the leakage of these dyes is a limitation for this methodology. Visualizing intercellular organelle transfer in real time in the intact living organism remains a major methodological challenge. The use of available cells and mice with fluorescent proteins confined to mitochondria will greatly accelerate the progress in this field (<a href="#B1">Abe et al., 2011</a>; <a href="#B67">Pham et al., 2012</a>). In addition, the use of mtDNA polymorphisms that allow the distinction of mtDNA from the donor and acceptor cells after mitochondria acquisition, the development of techniques to detect mitochondrial transfer (<a href="#B10">Caicedo et al., 2015</a>) and low levels of cell heteroplasmy in single cells from tissues, will help to unequivocally ascertain whether mitochondrial transfer occurs in the different scenarios. Importantly, the possible exchange of healthy mitochondria to sustain cells with OXPHOS deficiencies would prevent the manifestation of some diseases associated with mitochondrial dysfunction or with the heteroplasmic inheritance of mutated mtDNA. Hence, additional study is required to evaluate the real impact of these mechanisms in mitochondrial diseases.</p> <p class="mb15">The number of diseases in which impaired mitochondrial function is thought to contribute to pathogenesis is currently increasing. While the main strategy employed in the treatment of mitochondrial dysfunction involves targeting mitochondrial genes encoded by the nuclear genome, our current capacity to supplement, repair, or replace mitochondrial DNA in somatic cells is very limited (<a href="#B65">Patananan et al., 2016</a>).</p> <p class="mb15">Identification of the signaling pathways and the proteins controlling the transfer of mitochondria will improve its potential therapeutic application. Future therapeutic implications of this research need to consider strategies to pharmacologically enhance intercellular organelle transfer when desirable, or block its occurrence when it is deleterious, such as in the spread of infection or the maintenance of malignant cells. Given the considerable therapeutic potential of MSCs and mitochondrial transfer, future investigation of the mechanisms underlying the regulation of oxidative metabolism and dynamics of mitochondria in MSCs may ultimately facilitate the development of effective stem cell therapies for treatment of mitochondrial diseases. Elucidation of the mechanisms of mitochondrial transfer will help us create a potential cell therapy-based mitochondrial restoration or mitochondrial gene therapy for human diseases caused by mitochondrial dysfunction.</p> <p class="mb0">Another major concern pertains the required transfer dose. It might not be necessary to fully replace the mitochondria repertoire in the recipient cell to restore mitochondrial dysfunction. It is likely that the transfer of a low number of copies of a functional mtDNA could restore the normal copy number and therefore the mitochondrial function. Hence, tumors formed from cells with low copy number of mtDNA are able to recover them after injection into immunoincompetent mice (<a href="#B21">Dickinson et al., 2013</a>). This would open a new field in which mitochondrial transfer therapy would be an option to treat injured tissues, taking into account that using healthy mitochondria from the same patient could lead to a better performance of the tissues because of the matching between mitochondrial and nuclear DNA (<a href="#B46">Latorre-Pellicer et al., 2016</a>).</p> <a id="h6" name="h6"></a><h2>Author Contributions</h2> <p class="mb0">DT, FB, and FS: Elaboration and writing of the manuscript and making Figures. FS and FB contributed equally to this work.</p> <a id="h7" name="h7"></a><h2>Conflict of Interest Statement</h2> <p class="mb15">The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p> <p class="mb0">The reviewer RG and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.</p> <a id="h8" name="h8"></a><h2>Acknowledgments</h2> <p class="mb0">We thank Dr. Miguel Vicente-Manzanares and Carolina Villarroya-Beltri for their critical reading of the manuscript and editing. This study was supported by grants SAF2014-55579-R from the Spanish Ministry of Economy and Competitiveness, INDISNET-S2011/BMD-2332 from the Comunidad de Madrid, ERC-2011-AdG 294340-GENTRIS, Red Cardiovascular RD 12-0042-0056 and grant PIE13/00041 BIOIMID from Instituto Salud Carlos III (ISCIII). 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Cell Dev. Biol.</i> 4:107. doi: 10.3389/fcell.2016.00107</p> <p id="timestamps"><span>Received:</span> 01 August 2016; <span>Accepted:</span> 14 September 2016;<br> <span>Published:</span> 28 September 2016.</p> <div><p>Edited by:</p> <a href="http://loop.frontiersin.org/people/112503/overview">Jennifer L. Stow</a>, University of Queensland, Australia</div> <div><p>Reviewed by:</p> <a href="http://loop.frontiersin.org/people/36506/overview">Hilary Ann Coller</a>, University of California, Los Angeles, USA<br> <a href="http://loop.frontiersin.org/people/163095/overview">James Alan Marrs</a>, Indiana University – Purdue University Indianapolis, USA<br> <a href="http://loop.frontiersin.org/people/369318/overview">Rajesh Ghai</a>, University of Queensland, Australia</div> <p><span>Copyright</span> © 2016 Torralba, Baixauli and Sánchez-Madrid. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p> <p><span>*Correspondence:</span> Francisco Sánchez-Madrid, <a href="mailto:fsmadrid@salud.madrid.org">fsmadrid@salud.madrid.org</a></p> <p><span><sup>†</sup></span>These authors have contributed equally to this work.</p> <div class="clear"></div></div> </div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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It explores a wide spectrum of cell and developmental biology, covering intracellular and extracellular dynamics.",mission:"\u003Cp\u003EFrontiers in Cell and Developmental Biology is an interdisciplinary journal that focuses on the fundamental biological processes of life.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Prof Amanda Gay Fisher (University of Oxford, UK), this journal is indexed in PubMed Central (PMC), Scopus, Web of Science (SCIE), and the DOAJ, among others, and welcomes submissions on intracellular and extracellular dynamics.\u003C\u002Fp\u003E\n\n\u003Cp\u003EThe journal covers a wide spectrum of topics within cell and developmental biology including, but not limited to:\u003C\u002Fp\u003E\n\u003Cul\u003E\n \u003Cli\u003Ecancer cell biology\u003C\u002Fli\u003E\n \u003Cli\u003Ecell adhesion and migration\u003C\u002Fli\u003E\n \u003Cli\u003Ecell death and survival\u003C\u002Fli\u003E\n \u003Cli\u003Ecell growth and division\u003C\u002Fli\u003E\n \u003Cli\u003Ecellular biochemistry\u003C\u002Fli\u003E\n \u003Cli\u003Edevelopmental epigenetics\u003C\u002Fli\u003E\n \u003Cli\u003Eembryonic development\u003C\u002Fli\u003E\n \u003Cli\u003Eepigenomics and epigenetics\u003C\u002Fli\u003E\n \u003Cli\u003Eevolutionary developmental biology\u003C\u002Fli\u003E\n \u003Cli\u003Emembrane traffic\u003C\u002Fli\u003E\n \u003Cli\u003Emolecular and cellular pathology\u003C\u002Fli\u003E\n \u003Cli\u003Emolecular and cellular reproduction\u003C\u002Fli\u003E\n \u003Cli\u003Emorphogenesis and patterning\u003C\u002Fli\u003E\n \u003Cli\u003Enuclear organization and dynamics\u003C\u002Fli\u003E\n \u003Cli\u003Esignaling\u003C\u002Fli\u003E\n \u003Cli\u003Estem cell research.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003EIn addition, Frontiers in Cell and Developmental Biology is interested in fundamental and translational research in molecular medicine and stem cell biology. The journal also welcomes submissions which support and advance the UN鈥檚 Sustainable Development Goals (SDGs), notably SDG 3: good health and well-being.\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus solely on bioinformatics, computational analysis, or theoretical modeling without experimental validation are not suitable for publication in this journal. Additionally, studies that only report the therapeutic efficacy of certain compounds or treatments without providing insights into the underlying cellular and developmental biology mechanisms are not within the scope of this journal.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Cell and Developmental Biology is committed to advancing developments in the field by allowing unrestricted access to articles and communicating scientific knowledge to researchers and the public alike, to enable the scientific breakthroughs of the future.\u003C\u002Fp\u003E\n\n\u003Cp\u003EEthics Statement:\u003C\u002Fp\u003E\n\n\u003Cp\u003EAll manuscripts submitted to鈥疌ell and Developmental Biology that have been conducted in human subjects must conform with current regulations and the Declaration of Helsinki. Ethics committee approval and informed patient consent are required for studies involving human subjects. Ethics committee approval is also needed for studies involving animals. 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Authors should refer to the鈥痑uthor guidelines鈥痜or full details.\u003C\u002Fp\u003E",palette:"cyan",impactFactor:"5.5",citeScore:"6.3",citations:"149000",showTagline:e,twitter:"@FrontCellDevBio",__typename:"Journal"},currentFrontiersJournal:{id:r,name:m,slug:s,printISSN:e,shortName:E,electronicISSN:F,abbreviation:X,specialtyId:e,publicationDate:e,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:v,domainId:c,__typename:Y},__typename:a},articleHubSlug:g,articleHubPage:G,currentArticle:{id:223255,doi:Z,title:_,acceptanceDate:new Date(1473854483000),receptionDate:new Date(1470073653000),publicationDate:new Date(1475020800000),isPublished:h,abstract:$,researchTopic:{id:4462,title:"Extracellular microvesicles in immune cell communication",articlesCount:v,isMagazinePage:l,slug:"extracellular-microvesicles-in-immune-cell-communication",isOpenForSubmission:l},articleType:{id:27,name:"Review"},stage:{id:H,name:g},keywords:["horizontal genetic transfer","tunneling nanotubes","Mitochondrial Diseases","extracellular vesicles","Inflammation","DAMPs","Exosomes","Communication"],authors:[{id:aa,firstName:ab,lastName:"Torralba",givenNames:ab,isCorresponding:l,isProfilePublic:h,userId:aa,affiliations:[{organizationName:I,countryName:n,cityName:g,stateName:g,zipCode:g},{organizationName:J,countryName:n,cityName:g,stateName:g,zipCode:g}]},{id:ac,firstName:ad,lastName:"Baixauli",givenNames:ad,isCorresponding:l,isProfilePublic:h,userId:ac,affiliations:[{organizationName:I,countryName:n,cityName:g,stateName:g,zipCode:g},{organizationName:J,countryName:n,cityName:g,stateName:g,zipCode:g}]},{id:ae,firstName:af,lastName:"S谩nchez-Madrid",givenNames:af,isCorresponding:h,isProfilePublic:h,userId:ae,affiliations:[{organizationName:I,countryName:n,cityName:g,stateName:g,zipCode:g},{organizationName:J,countryName:n,cityName:g,stateName:g,zipCode:g}]}],editors:[{id:ag,firstName:"Jennifer",lastName:"Stow",givenNames:"Jennifer L",isCorresponding:l,isProfilePublic:h,userId:ag,affiliations:[{organizationName:ah,countryName:ai,cityName:g,stateName:g,zipCode:g}]}],reviewers:[{id:aj,firstName:"Hilary",lastName:"Coller",givenNames:"Hilary Ann",isCorresponding:l,isProfilePublic:h,userId:aj,affiliations:[{organizationName:"University of California, Los Angeles",countryName:ak,cityName:g,stateName:g,zipCode:g}]},{id:al,firstName:"James",lastName:"Marrs",givenNames:"James Alan",isCorresponding:l,isProfilePublic:h,userId:al,affiliations:[{organizationName:"Indiana University, Purdue University Indianapolis",countryName:ak,cityName:g,stateName:g,zipCode:g}]},{id:am,firstName:an,lastName:"Ghai",givenNames:an,isCorresponding:l,isProfilePublic:h,userId:am,affiliations:[{organizationName:ah,countryName:ai,cityName:g,stateName:g,zipCode:g}]}],journal:{id:r,slug:s,name:m,shortName:E,electronicISSN:F,field:{id:v,domainId:c,__typename:Y},specialtyId:e,journalSectionPaths:[{section:ao,__typename:"journal_journalSectionPath"}],__typename:a},section:ao,impactMetrics:{views:38740,downloads:10200,citations:327},volume:o,articleVolume:"Volume 4 - 2016",relatedArticles:[],isPublishedV2:l,contents:{fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\r\n\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\u003Ch1\u003EMitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer\u003C\u002Fh1\u003E\r\n\u003Cdiv class=\"authors\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F374612\" class=\"user-id-374612\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F374612\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" \u002F\u003EDaniel Torralba\u003C\u002Fa\u003E\u003Csup\u003E1,2\u003C\u002Fsup\u003E, \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F177508\" class=\"user-id-177508\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F177508\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" \u002F\u003EFrancesc Baixauli\u003C\u002Fa\u003E\u003Csup\u003E1,2\u003C\u002Fsup\u003E\u003Csup\u003E†\u003C\u002Fsup\u003E and \u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Fpeople\u002Fu\u002F17933\" class=\"user-id-17933\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F17933\u002F24\" onerror=\"this.src='http:\u002F\u002F3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com\u002FDesign\u002FImages\u002Fnewprofile_default_profileimage_new.jpg'\" \u002F\u003EFrancisco Sánchez-Madrid\u003C\u002Fa\u003E\u003Csup\u003E1,2\u003C\u002Fsup\u003E\u003Csup\u003E*\u003C\u002Fsup\u003E\u003Csup\u003E†\u003C\u002Fsup\u003E\u003C\u002Fdiv\u003E\r\n\u003Cul class=\"notes\"\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ESignaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares, Madrid, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EServicio de Inmunología, Instituto Investigación Sanitaria Princesa, Universidad Autonoma de Madrid, Madrid, Spain\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n\u003Cp\u003EMitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome encoding selected subunits of the oxidative phosphorylation complexes. Recent findings reveal that, in addition to being maternally inherited, mitochondria can traverse cell boundaries and thus be horizontally transferred between cells. Although, the physiological relevance of this phenomenon is still under debate, mitochondria uptake rescues mitochondrial respiration defects in recipient cells and regulates signaling, proliferation or chemotherapy resistance \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E. In this review, we outline the pathophysiological consequences of horizontal mitochondrial transfer and offer a perspective on the cellular and molecular mechanisms mediating their intercellular transmission, including tunneling nanotubes, extracellular vesicles, cellular fusion, and GAP junctions. The physiological relevance of mitochondrial transfer and the potential therapeutic application of this exchange for treating mitochondrial-related diseases are discussed.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"JournalFullText\"\u003E\r\n\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EMitochondria regulate cellular homeostasis by controlling energy production, calcium signaling, cell metabolism and apoptosis. According to the endosymbiotic theory, mitochondria are derived from eubacteria that engaged in a symbiotic relationship with primitive host cells. They have maintained some of their ancestral bacterial characteristics, such as a double membrane, a proteome similar to the α-proteobacteria, and the ability to generate the majority of ATP from cells in the process of aerobic respiration or oxidative phosphorylation (OXPHOS) (\u003Ca href=\"#B24\"\u003EFriedman and Nunnari, 2014\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EMitochondria are endowed with their own circular genome, which is 16.6 kb in length in mammalian cells. This mitochondrial DNA (mtDNA) encodes 13 subunits that are essential components of the electron transport chain, and a translational system made of two ribosomal RNAs and 22 tRNAs, required for the translation of these proteins (\u003Ca href=\"#B31\"\u003EGustafsson et al., 2016\u003C\u002Fa\u003E). During evolution, most of the mitochondrial ancestor genes have been progressively transferred to the nuclear genome, or lost; while mitochondria have acquired new components and functions from the host cell (\u003Ca href=\"#B42\"\u003EKeeling and Palmer, 2008\u003C\u002Fa\u003E). A typical mammalian cell contains thousands of copies of the mitochondrial genome, which are organized in mtDNA-protein complexes known as nucleoids (\u003Ca href=\"#B45\"\u003EKukat et al., 2015\u003C\u002Fa\u003E). The mitochondrial genome copies of a given cell can be identical (homoplasmy), or contain more variants (heteroplasmy). Although it was generally assumed that healthy individuals exhibit homoplasmy for a single mtDNA genotype, next-generation sequencing has revealed the presence of low-level heteroplasmy in most tissues from healthy individuals (\u003Ca href=\"#B35\"\u003EHe et al., 2010\u003C\u002Fa\u003E; \u003Ca href=\"#B66\"\u003EPayne et al., 2013\u003C\u002Fa\u003E). The source of this heteroplasmy is likely to be maternally inherited, as some of the low-frequency alleles found in an individual can also be found in the mother. They may also stem from somatic mutations that occur during tissue development and aging. In inherited mitochondrial DNA diseases, individuals are typically heteroplasmic and harbor both wild-type and pathogenic mtDNA molecules. Although, cells can tolerate a heavy load of pathogenic mutations, these will lead to disease when the mutation load surpasses a tolerable threshold, causing multisystemic diseases that specially affect organs with high energy requirements such as the brain, muscle, and heart. Additionally, many somatic mutations in mtDNA are related to a number of other pathologies such as cancer, cardiovascular diseases and neurodegenerative disorders, as well as the normal aging process (\u003Ca href=\"#B91\"\u003EWallace, 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EIn mammals, mitochondria are transmitted to subsequent generations exclusively through the maternal lineage. Uniparental germline inheritance reduces the benefits of recombination arising from sexual reproduction, also facilitating the appearance of maternally inherited disorders when a significant amount of mtDNA mutations are transmitted to the offspring. To counteract this, the mtDNA population undergoes a restricted process of purifying selection during oogenesis, allowing only a small population of mtDNA molecules to be amplified and transmitted. Moreover, selective replication and degradation can expand a subpopulation of mtDNA molecules at the expense of others, leading to the rapid segregation of mtDNA variants within a few generations (\u003Ca href=\"#B81\"\u003EStewart and Larsson, 2014\u003C\u002Fa\u003E). During somatic cell proliferation, symmetric cell division implies that mitochondria and mtDNA are distributed between both daughter cells. Segregation of mitochondria and mtDNA involves mitochondrial fission, facilitated by the interaction of mitochondria with cytoskeletal and endoplasmic reticulum elements (\u003Ca href=\"#B23\"\u003EFriedman et al., 2011\u003C\u002Fa\u003E; \u003Ca href=\"#B47\"\u003ELewis et al., 2016\u003C\u002Fa\u003E). Mitochondrial partitioning during symmetric division can be envisioned as a stochastic process in which mitochondrial subunits are distributed randomly between daughter cells. Conversely, recent findings suggest that asymmetric cell division differentially segregates young and old mitochondria, revealing the existence of active mechanisms that guide mitochondria partitioning between daughter cells (\u003Ca href=\"#B41\"\u003EKatajisto et al., 2015\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003ESeveral mechanisms maintain the integrity of mitochondria and mitochondrial genome in post-mitotic cells. Constant cycles of fusion and fission promote the intermixing and the homogenization of mitochondrial proteins, lipids and DNA between discrete organelles within the same cell (\u003Ca href=\"#B54\"\u003EMishra and Chan, 2014\u003C\u002Fa\u003E). Consistent with this, cells lacking proteins involved in mitochondrial dynamics, e.g., mitofusins, show a striking heterogeneity among mitochondria in terms of protein and mtDNA nucleoid content, and membrane potential (\u003Ca href=\"#B12\"\u003EChen et al., 2010\u003C\u002Fa\u003E). This causes defects in the respiratory chain function and promotes the accumulation of mtDNA mutations. The selective elimination of mitochondria through mitophagy eliminates deleterious mitochondrial mutations in heteroplasmic cells, restoring ATP levels and mitochondrial functions (\u003Ca href=\"#B82\"\u003ESuen et al., 2010\u003C\u002Fa\u003E; \u003Ca href=\"#B17\"\u003EDai et al., 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B87\"\u003EValenci et al., 2015\u003C\u002Fa\u003E). However, increased mitochondrial biogenesis in heteroplasmic cells replenishes the amount of deleterious mtDNA (\u003Ca href=\"#B27\"\u003EGitschlag et al., 2016\u003C\u002Fa\u003E; \u003Ca href=\"#B49\"\u003ELin et al., 2016\u003C\u002Fa\u003E). Therefore, specific mechanisms regulate the stability and transmission of mitochondria and their genome during germline transmission and somatic cell proliferation. This is enabled by purifying selection and selective replication or degradation of mtDNA. In non-dividing cells, the dynamics of mitochondrial networks and their selective degradation or biogenesis maintains a healthy mitochondria repertoire.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EMitochondria have been recently shown to be horizontally transferred between mammalian cells, challenging current concepts of mitochondria and mtDNA segregation and inheritance. This transfer promotes the incorporation of mitochondria into the endogenous mitochondrial network of recipient cells, contributing to changes in the bioenergetic profile and in other functional properties of recipient cells, not only \u003Ci\u003Ein vitro\u003C\u002Fi\u003E but also \u003Ci\u003Ein vivo\u003C\u002Fi\u003E. Moreover, intercellular transfer of mitochondria involves the horizontal transfer of mitochondrial genes, which has important implications in the physiopathology of mitochondrial dysfunction. The intercellular transfer of mitochondria or their components, may also result in the initiation of stem cell differentiation, reprogramming of differentiated cells, or activation of inflammatory signaling pathways. Diverse structures mediate intercellular mitochondrial transfer. These include tunneling nanotubes (TNTs), microvesicles, mitochondrial ejection or cytoplasmic fusion, among others. Future research in this field is likely to open new avenues for the treatment of mitochondrial related disorders, e.g., transfer of healthy, or genetically corrected, mitochondria.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EIn this review, we discuss the relevance of mitochondrial transfer in physiological processes. Starting from an integrated view of the molecular mechanisms mediating intercellular mitochondrial transmission, we delve into the pathophysiological consequences of horizontal mitochondrial transfer. Finally, we discuss how intercellular mitochondrial transfer can be exploited as a new avenue for the treatment of mitochondrial-related diseases.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntercellular Mitochondrial Transfer\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EThe existence of nanotubular structures mediating the transfer of many cellular constituents (\u003Ca href=\"#B76\"\u003ERustom et al., 2004\u003C\u002Fa\u003E) has demonstrated the widespread ability of mammalian cells to donate or receive organelles from other cells (\u003Ca href=\"#B26\"\u003EGerdes et al., 2007\u003C\u002Fa\u003E; \u003Ca href=\"#B20\"\u003EDavis and Sowinski, 2008\u003C\u002Fa\u003E). Such transfer involves many different cell types \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E, including lymphocytes, neurons or cardiomyocytes. Organelle exchange represents a special form of intercellular communication that allows unidirectional or bidirectional transfer, not only of signals, small molecules or ions, but also of defined intracellular structures such as mitochondria, lysosomes, endosomal vesicles and plasma membrane components (\u003Ca href=\"#B75\"\u003ERogers and Bhattacharya, 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EThe first evidence of functional mitochondrial transfer involved healthy mitochondria from human stem cells rescuing mitochondrial respiration in mitochondria-depleted recipient cells (\u003Ca href=\"#B79\"\u003ESpees et al., 2006\u003C\u002Fa\u003E). Cells devoid of intrinsic mitochondrial function by mtDNA depletion through long-term ethidium bromide treatment, do not survive in standard media. However, when these cells were co-cultured with mesenchymal stem cells (MSCs) or fibroblasts that donated functional mitochondria, they acquired mitochondria and re-established aerobic respiration. The careful examination of mitochondrial and nuclear DNA polymorphisms in the rescued clones excluded cell fusion as the main mechanism of mitochondrial transfer, also confirming the stem cell origin of the transferred mtDNA (\u003Ca href=\"#B79\"\u003ESpees et al., 2006\u003C\u002Fa\u003E). Transfer did not occur through the passive uptake of mitochondrial fragments or isolated organelles, but rather involved active processes such as the formation of TNTs and\u002For the vesicular transfer of mtDNA or mitochondrial fragments.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EOther groups have demonstrated that the horizontal cell-to-cell transfer of mitochondria and mitochondrial genome can occur among many other mammalian cells \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E (\u003Ca href=\"#B7\"\u003EBerridge et al., 2016\u003C\u002Fa\u003E). Mitochondrial transfer supports the exogenous replacement of damaged mitochondria, thereby rescuing mitochondrial defects (\u003Ca href=\"#B33\"\u003EHayakawa et al., 2016\u003C\u002Fa\u003E; \u003Ca href=\"#B65\"\u003EPatananan et al., 2016\u003C\u002Fa\u003E). Most studies used stem cells as mitochondrial donors, but some others also used immortalized cells or primary cells from the same or different species (\u003Ca href=\"#B7\"\u003EBerridge et al., 2016\u003C\u002Fa\u003E). Although, there are some concerns regarding whether intercellular mitochondrial transfer is a physiologically relevant process or it is only observed in cell culture conditions, recent evidence strongly supports that mitochondrial transfer does occur \u003Ci\u003Ein vivo\u003C\u002Fi\u003E and may be involved in diverse pathophysiological situations, such as tissue injury and cancer progression (\u003Ca href=\"#B37\"\u003EIslam et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B4\"\u003EAhmad et al., 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B84\"\u003ETan et al., 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B33\"\u003EHayakawa et al., 2016\u003C\u002Fa\u003E; \u003Ca href=\"#B57\"\u003EMoschoi et al., 2016\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EIntercellular mitochondrial transfer rescues injured cells from mitochondrial dysfunctions related with several models of cell survival associated to stress responses. MSC improve survival and restore cell damage by transferring their mitochondria through TNTs to EC or cardiomyocytes previously subjected to an \u003Ci\u003Ein vitro\u003C\u002Fi\u003E model of ischemia-reperfusion, in which cells are cultured under glucose-oxygen deprivation and then reoxygenated (\u003Ca href=\"#B50\"\u003ELiu et al., 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B32\"\u003EHan et al., 2016\u003C\u002Fa\u003E). Similarly, the transfer of mitochondria from MSC to human umbilical vein endothelial cells (HUVEC) previously subjected to \u003Ci\u003Ein vitro\u003C\u002Fi\u003E ischemia-reperfusion, restores aerobic respiration in EC independently of cellular trans-differentiation or the release of paracrine factors. Notably, aerobic restoration is not reestablished in HUVEC when these are cultured alone or with MSCs containing dysfunctional mitochondria promoted by mtDNA depletion (\u003Ca href=\"#B50\"\u003ELiu et al., 2014\u003C\u002Fa\u003E). Interestingly, phosphatidylserine exposure on injured endothelial cells acts as a “find-me” signal that triggers the emergence of tunneling nanotubes and guides them from MSC to injured HUVECs (\u003Ca href=\"#B50\"\u003ELiu et al., 2014\u003C\u002Fa\u003E). Mitochondrial transfer from MSCs to lung epithelium also attenuates cigarette smoke-induced lung damage (\u003Ca href=\"#B48\"\u003ELi et al., 2014\u003C\u002Fa\u003E), while transfer between MSC and innate immune cells via TNTs and microvesicle secretion enhances the capacity of alveolar macrophages to engulf invading bacteria in an \u003Ci\u003EE.coli\u003C\u002Fi\u003E pneumonia model (\u003Ca href=\"#B38\"\u003EJackson et al., 2016\u003C\u002Fa\u003E). Based on these results, it has been proposed that cell stress is required for organelle transfer. Mitochondrial transfer is triggered by an almost complete absence of mitochondrial function, such as mtDNA depletion or treatment with mitochondrial inhibitors, since transfer is not detected to cells harboring pathogenic mutations that partially affect mitochondrial function (\u003Ca href=\"#B13\"\u003ECho et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B92\"\u003EWang and Gerdes, 2015\u003C\u002Fa\u003E). An intriguing question pertains to the degree of cellular damage required to initiate intercellular transfer of functional mitochondria. We also ponder about the mechanisms by which the healthy cell detects the degree of metabolic shutdown of the stressed cell and makes a “judgment call” to restore the functionality of the stressed cell, instead of permitting apoptosis to remove the damaged cell. This would be of particular interest in non-replaceable cell lineages such as adult neurons. Accordingly, the transfer of mitochondria from astrocytes to neurons has a neuroprotective effect after stroke (\u003Ca href=\"#B33\"\u003EHayakawa et al., 2016\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EMitochondrial transfer seems to be involved in stem cell-triggered repair of damaged cells (\u003Ca href=\"#B71\"\u003EPlotnikov et al., 2008\u003C\u002Fa\u003E). Mitochondrial transfer from stem cells to lung epithelial cells and endothelial cells is an important mechanism by which MSC exert their protective effects in several animal models of lung diseases. A seminal study demonstrated that transfer of intact mitochondria can contribute to tissue repair \u003Ci\u003Ein vivo\u003C\u002Fi\u003E (\u003Ca href=\"#B37\"\u003EIslam et al., 2012\u003C\u002Fa\u003E). In that study, bone marrow-derived stem cells (BMSCs) infused to the trachea of lipopolysaccharides (LPS)-treated mice attached to injured alveolar epithelial cells by a mechanism involving connexins (Figure \u003Ca href=\"#F1\"\u003E1\u003C\u002Fa\u003E). Connexin oligomerization forms channels or GAP junctions that connect two cells, allowing the transfer of only small metabolites, ions or small RNAs. Connexins, and specifically connexin-43, regulate intercellular mitochondrial transfer by promoting the attachment of BMSCs to LPS-injured alveolar epithelial cells, leading to the formation of nanotubes and microvesicles that mediate mitochondrial transfer. Mitochondria acquisition by the alveolar cells triggered the restoration of ATP levels and increased the secretion of pulmonary surfactant. Silencing of RISP, a subunit of the mitochondrial complex III, in BMSCs reduced their capacity to restore ATP levels in recipient alveolar epithelial cells, avoiding protection from LPS-injury (\u003Ca href=\"#B37\"\u003EIslam et al., 2012\u003C\u002Fa\u003E). These results implicated mitochondrial transfer as a driver of the \u003Ci\u003Ein vivo\u003C\u002Fi\u003E benefits of mesenchymal stem cell therapy in models of acute lung injury and other inflammatory diseases, enhancing cellular bioenergetics and improving organ function. A follow-up study in mice provided a molecular mechanism to potentially increase the therapeutic efficiency of MSC by modulating the extent of mitochondrial transfer (\u003Ca href=\"#B4\"\u003EAhmad et al., 2014\u003C\u002Fa\u003E). This study described that the levels of Miro1, a protein connecting mitochondria to cytoskeletal motor proteins, regulate the efficiency of intercellular movement of mitochondria. Hence, overexpression of Miro1 in MSC increased mitochondrial transfer from stem cells into stressed epithelial cells via intercellular TNTs, attenuating epithelial cell apoptosis and reducing inflammatory cell infiltration, collagen deposition and mucus hypersecretion in the lungs. Overall, Miro1 overexpression improves the therapeutic efficiency of mitochondrial transfer across multiple models of asthma \u003Ci\u003Ein vivo\u003C\u002Fi\u003E and \u003Ci\u003Ein vitro\u003C\u002Fi\u003E (\u003Ca href=\"#B4\"\u003EAhmad et al., 2014\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F223255\u002Ffcell-04-00107-HTML\u002Fimage_m\u002Ffcell-04-00107-g001.jpg\" name=\"figure1\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F223255\u002Ffcell-04-00107-HTML\u002Fimage_t\u002Ffcell-04-00107-g001.gif\" id=\"F1\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 1. Cellular mechanisms of intercellular mitochondrial transfer. (A)\u003C\u002Fstrong\u003E \u003Ci\u003ETunneling nanotubes\u003C\u002Fi\u003E (TNT) are long ultrathin structures with diameters ranging from 50 to 200 nm and a length that allow organelle transfer between two spatially separated cells. TNTs contain cytoskeletal elements such as actin and microtubules depending on the cell type. Myosin is a fundamental protein for the organelle transfer, a process where high rates of ATP consumption are needed. Rho GTPases play an important role in organelle transfer through TNT. Miro1 and microtubules have been involved in the transfer of mitochondria upon injury (\u003Ca style=\"color:grey;\" href=\"#B4\"\u003EAhmad et al., 2014\u003C\u002Fa\u003E). \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E \u003Ci\u003ECell fusion\u003C\u002Fi\u003E is a process, in which two independent cells fuse their membranes and share organelles and cytosolic compounds, however nuclei remain intact. Cell fusion can be transitory and therefore lose their integrity transiently or complete, where cells will share cytoplasm continuously, for example in muscle cells. It has been shown that after myocardial infarct stem cell therapy can lead to a better recovery and it is proved that partial or total fusion events can happen between cardiomyocytes and stem cells (\u003Ca style=\"color:grey;\" href=\"#B61\"\u003EOh et al., 2003\u003C\u002Fa\u003E). By this mechanism mitochondrial respiration can be restored and this could be an indicative marker for cardiac regeneration after infarct. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E \u003Ci\u003EGAP junctions\u003C\u002Fi\u003E. LPS treatment increases connexin 43 expression in alveolar cells. Connexins facilitate the attachment of BMSC to the alveolar epithelial cells, and produce vesicles and nanotubes to share mitochondria with the damaged cells protecting against acute lung injury (\u003Ca style=\"color:grey;\" href=\"#B37\"\u003EIslam et al., 2012\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cp class=\"mb0 w100pc float_left mt15\"\u003ECancer cells opportunistically acquire mitochondria to optimize or repair their metabolic machinery. In this regard, horizontal transfer of mtDNA from host cells to tumor cells with compromised respiratory function has been described (\u003Ca href=\"#B84\"\u003ETan et al., 2015\u003C\u002Fa\u003E). Tumor cells devoid of mtDNA, a model of extreme mtDNA damage, acquire mtDNA from surrounding donor healthy cells, repairing the transcriptional and translational activity of mtDNA-encoded genes and triggering a substantial recovery of mitochondrial respiration, as well as tumor initiation efficacy and metastasis capacity. A major source of healthy mitochondria in these contexts are stromal cells, which can modulate the phenotype of the tumor by direct mitochondria transfer. Cancer cells and stromal cells communicate through TNTs, and mitochondrial transfer via TNTs from endothelial to cancer cells enhances their chemoresistance to doxorubicin \u003Ci\u003Ein vitro\u003C\u002Fi\u003E (\u003Ca href=\"#B64\"\u003EPasquier et al., 2013\u003C\u002Fa\u003E). In addition, mitochondrial transfer from bone marrow mesenchymal cells to acute myelogenous leukemia cells \u003Ci\u003Ein vivo\u003C\u002Fi\u003E confers chemoresistance and survival advantage (\u003Ca href=\"#B57\"\u003EMoschoi et al., 2016\u003C\u002Fa\u003E). These findings highlight the requirement of mitochondrial respiration for tumorigenesis and metastasis, and support mitochondrial transfer as a mechanism for the efficient metabolic adaptation of tumor cells to hostile microenvironments (\u003Ca href=\"#B84\"\u003ETan et al., 2015\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch3\u003EMitochondrial Transfer beyond Cell Rescue\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003EIntercellular organelle transfer participates in cell differentiation and\u002For de-differentiation (\u003Ca href=\"#B71\"\u003EPlotnikov et al., 2008\u003C\u002Fa\u003E, \u003Ca href=\"#B70\"\u003E2010\u003C\u002Fa\u003E). Human adipose-derived or bone marrow-derived stem cells can reprogram differentiated mouse cardiomyocytes into a progenitor-like state. This process involves partial cell fusion and mitochondrial transfer. Deprivation of mtDNA in stem cells dramatically decreased the efficiency of the reprogramming process. Although, mtDNA depletion may affect cell stemness and the ability to donate mitochondria, these results suggest that mitochondrial transfer from stem cells to adult cardiomyocytes helps their conversion to the progenitor state through metabolic reprogramming (\u003Ca href=\"#B2\"\u003EAcquistapace et al., 2011\u003C\u002Fa\u003E). Stem cell interaction with other cell types does not necessarily result in actual differentiation, but it may rather initiate a proliferative response, as observed during mitochondrial transfer from vascular smooth muscle cells to MSCs (\u003Ca href=\"#B88\"\u003EVallabhaneni et al., 2012\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EThe release of mitochondria or mitochondrial components into the extracellular space has important immune consequences. After an episode of acute injury, release of mitochondrial components into the extracellular medium and bloodstream may trigger potent pro-inflammatory responses. In fact, mitochondrial components can be recognized by cells of the immune system as damage-associated molecular patterns (DAMPs) (\u003Ca href=\"#B99\"\u003EZhang et al., 2010\u003C\u002Fa\u003E; \u003Ca href=\"#B25\"\u003EGalluzzi et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B96\"\u003EWest et al., 2015\u003C\u002Fa\u003E). Different mitochondrial proteins such as TFAM, together with other mitochondrial DAMPs like N-formyl peptides, mtDNA, cardiolipin or extracellular ATP, robustly activate the inflammatory response (\u003Ca href=\"#B95\"\u003EWeinberg et al., 2015\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EMitochondrial DNA induces inflammation when found beyond mitochondrial membrane boundaries (\u003Ca href=\"#B99\"\u003EZhang et al., 2010\u003C\u002Fa\u003E). Mitochondrial DNA injected directly into mice joints causes inflammation and arthritis (\u003Ca href=\"#B15\"\u003ECollins et al., 2004\u003C\u002Fa\u003E). Moreover, mitochondrial DNA that escapes autophagy leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in a cell-autonomous manner (\u003Ca href=\"#B62\"\u003EOka et al., 2012\u003C\u002Fa\u003E). When abnormally found in the cytosol, mtDNA triggers NRLP3-inflammasome activation and STING-dependent antiviral signaling (\u003Ca href=\"#B78\"\u003EShimada et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B96\"\u003EWest et al., 2015\u003C\u002Fa\u003E), which ultimately leads to cell death. Neutrophils release to the extracellular environment oxidized mitochondrial nucleoids that activate the interferon response in pathological situations such as human systemic lupus erythematosus (\u003Ca href=\"#B11\"\u003ECaielli et al., 2016\u003C\u002Fa\u003E), whereas activated platelets release into the bloodstream entire mitochondria or mitochondria encapsulated in microparticles to boost the inflammatory response (\u003Ca href=\"#B8\"\u003EBoudreau et al., 2014\u003C\u002Fa\u003E). Interestingly, mtDNA released by eosinophils or basophils contribute to inflammatory responses creating DNA net traps to fight against invading pathogens (\u003Ca href=\"#B98\"\u003EYousefi et al., 2008\u003C\u002Fa\u003E; \u003Ca href=\"#B56\"\u003EMorshed et al., 2014\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EMitochondria-dependent activation of the inflammatory response has important consequences to understand intercellular mitochondrial transfer. In this regard, innate immune cells target cells containing allogenic mtDNA (\u003Ca href=\"#B36\"\u003EIshikawa et al., 2010\u003C\u002Fa\u003E). Such recognition mechanism, displayed by natural killer cells and dendritic cells, is not yet understood, but it is likely to control the extent of intercellular mitochondrial transfer in pathophysiological conditions. As a consequence, careful modulation of immune surveillance mechanisms in recipient cells could be a potential strategy to boost exogenous mitochondrial donation for therapeutic purposes. Consistent with this view, MSC secrete microvesicles containing depolarized mitochondria that are engulfed by macrophages in the stem cell niche (\u003Ca href=\"#B68\"\u003EPhinney et al., 2015\u003C\u002Fa\u003E). Together with microvesicles, MSC secrete exosomes that inhibit TLR signaling and macrophage activation, thereby promoting specific tolerance to the transferred mitochondria. Also, mitochondrial transfer by MSCs may enhance their own survival by unloading partially depolarized mitochondria into more professional phagocytic cells such as macrophages (\u003Ca href=\"#B68\"\u003EPhinney et al., 2015\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EA similar process of transcellular degradation of transferred mitochondria (“transmitophagy”) has been observed in neurons at the optic nerve head (ONH). Axonal protrusions and evulsions within the ONH contain mitochondria that are shed from neurons and degraded by the lysosomes of neighboring astrocytes (glial cells) (\u003Ca href=\"#B18\"\u003EDavis et al., 2014\u003C\u002Fa\u003E). This process accounts for the majority of mitochondrial turnover, rather than mitophagy in the ganglion cell soma. The most likely reason for this mechanism is that it is energetically taxing to transport axonal mitochondria back to the soma for degradation. The system thus takes advantage of the presence of a subset of astrocytes with extreme phagocytic activity on the ONH (\u003Ca href=\"#B19\"\u003EDavis and Marsh-Armstrong, 2014\u003C\u002Fa\u003E). In agreement, astrocytes can phagocytose whole synapses (\u003Ca href=\"#B14\"\u003EChung et al., 2013\u003C\u002Fa\u003E). A similar autophagy-assisted phagocytosis is also involved in the turnover of photoreceptor outer segments by retinal pigment epithelial cells (\u003Ca href=\"#B44\"\u003EKim et al., 2013\u003C\u002Fa\u003E). Although, transmitophagy is a relatively novel process in the nervous system, similar transcellular degradation of mitochondria occurs in gametes upon fertilization, in which sperm mitochondria are actively degraded by oocytes by the same molecular machinery used in autophagy (\u003Ca href=\"#B5\"\u003EAl Rawi et al., 2011\u003C\u002Fa\u003E; \u003Ca href=\"#B77\"\u003ESato and Sato, 2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch3\u003EHorizontal Gene Transfer\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003EAlthough widely observed in prokaryotes, horizontal gene transfer (HGT) is in general a rare phenomenon in metazoans. However, HGT in eukaryotes might be less rare than previously anticipated (\u003Ca href=\"#B16\"\u003ECrisp et al., 2015\u003C\u002Fa\u003E), and it has likely contributed to biochemical diversification during animal evolution. The horizontal transfer of genetic material between species of \u003Ci\u003ESaccharomyces\u003C\u002Fi\u003E has been postulated during the evolution of modern yeast species (\u003Ca href=\"#B53\"\u003EMarinoni et al., 1999\u003C\u002Fa\u003E). Likewise, asexual bdelloid rotifers have experienced extensive HGT from non-metazoan genes (\u003Ca href=\"#B28\"\u003EGladyshev et al., 2008\u003C\u002Fa\u003E), which might have compensated the lack of genetic heterogeneity due to the absence of sexual recombination (\u003Ca href=\"#B22\"\u003EEyres et al., 2015\u003C\u002Fa\u003E). One interesting example is the horizontal transfer of entire genomes via mitochondrial fusion in the angiosperm \u003Ci\u003EAmborella\u003C\u002Fi\u003E. Specifically, \u003Ci\u003EAmborella\u003C\u002Fi\u003E mtDNA includes a diverse collection of foreign sequences corresponding to about six genome equivalents of mtDNA acquired from mosses, angiosperms and green algae (\u003Ca href=\"#B74\"\u003ERice et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EOne of the first evidences of \u003Ci\u003Ein vivo\u003C\u002Fi\u003E horizontal mitochondrial gene transfer was found in a transmissible canine venereal tumor (CTVT), which is a highly adapted form of cancer that is transmitted as an allograft during mating of feral dogs. Phylogenetic evidence supports that CTVT cells periodically acquire mitochondria from their hosts to support long-term survival. Gene transfer events might rescue CTVT mitochondrial function, allowing the tumor to overcome the high mutation rate that would promote the accumulation of deleterious mutations in their own mitochondria (\u003Ca href=\"#B72\"\u003ERebbeck et al., 2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EThe intercellular exchange of mtDNA for the maintenance of heteroplasmy in cells has been recently proposed (\u003Ca href=\"#B39\"\u003EJayaprakash et al., 2015\u003C\u002Fa\u003E). Heteroplasmy is maintained in individual daughter cells over multiple cell divisions, which suggests the existence of active mechanisms that counteract mtDNA drift toward homoplasmy. Using a novel method to enzymatically purify mtDNA, the authors demonstrate the intercellular transfer of mtDNA between cell lines with distinct mtDNA haplotypes in co-culture experiments (\u003Ca href=\"#B39\"\u003EJayaprakash et al., 2015\u003C\u002Fa\u003E), raising the intriguing possibility that horizontal mtDNA exchange may regulate heteroplasmy \u003Ci\u003Ein vivo\u003C\u002Fi\u003E.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ECellular Structures Mediating Intercellular Mitochondrial Transfer\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe molecular and signaling mechanisms by which cells containing dysfunctional mitochondria acquire mitochondria from other cells, and how this process is regulated remain unclear. Cells likely possess mechanisms to trigger organelle exchange in response to injury signals emanating from the recipient cell. However, the molecular cues that initiate such crosstalk are still unidentified. Tunneling nanotubes are seen so far as the main cellular structure that mediates intercellular mitochondrial transfer. Other mechanisms have been proposed, including membrane microvesicles, cell fusion or mitochondrial ejection. Transfer through these diverse structures may result in different functional outcomes for the recipient cells, i.e., functional mitochondrial acquisition, immune activation or transmitophagy. Thus, a clear understanding on the mechanisms mediating mitochondrial transmission will shed light on how mitochondrial transfer is regulated and can be exploited for therapeutic purposes.\u003C\u002Fp\u003E\r\n\u003Ch3\u003ETunneling Nanotubes\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003ETunneling nanotubes (TNTs) form between different cell types \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E (Figure \u003Ca href=\"#F1\"\u003E1\u003C\u002Fa\u003E). Tunneling nanotubes facilitate the selective exchange of organelle or membrane vesicles and small soluble cytoplasmic and membrane molecules. The establishment of a nanotube begins with the formation of a filopodium-like membrane protrusion that retracts after reaching the receptor cell, leaving an ultrafine structure that is separated from the substrate. TNTs appear to be essential for effective mitochondrial transfer, since impairing TNT formation with chemical inhibitors or mechanical stress reduces mitochondrial exchange, whereas inhibition of phagocytosis, endocytosis or exocytosis have little or no effect (\u003Ca href=\"#B9\"\u003EBukoreshtliev et al., 2009\u003C\u002Fa\u003E). Transfer of mitochondria through TNTs is usually unidirectional, from the cell that initiated the formation of TNT to the receptor cell (\u003Ca href=\"#B76\"\u003ERustom et al., 2004\u003C\u002Fa\u003E; \u003Ca href=\"#B9\"\u003EBukoreshtliev et al., 2009\u003C\u002Fa\u003E). However, bidirectional transfer has also been reported (\u003Ca href=\"#B34\"\u003EHe et al., 2011\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003ECertain types of stress agents increase TNT formation and mitochondrial transfer. Doxorubicin treatment increases mitochondrial transfer from endothelial progenitors to mature endothelial cells challenged with doxorubicin (\u003Ca href=\"#B97\"\u003EYasuda et al., 2010\u003C\u002Fa\u003E), while ethidium bromide treatment enhances mitochondrial transfer from MSC to osteosarcoma-treated cells (\u003Ca href=\"#B13\"\u003ECho et al., 2012\u003C\u002Fa\u003E). Similarly, multipotent mesenchymal stem cells transfer mitochondria to lung epithelium cells treated with cigarette smoke (\u003Ca href=\"#B48\"\u003ELi et al., 2014\u003C\u002Fa\u003E). \u003Ci\u003EIn vivo\u003C\u002Fi\u003E, acute lung injury promoted either by rotenone or TNF-treatment is required for the transfer of mitochondria from stem cells to lung epithelial cells (\u003Ca href=\"#B4\"\u003EAhmad et al., 2014\u003C\u002Fa\u003E). In general, mitochondrial damage is the main trigger of TNT-based mitochondrial transfer (Figure \u003Ca href=\"#F1\"\u003E1\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EOther conditions that favor TNT formation are serum starvation and hydrogen peroxide. These conditions activate p53 and nanotube formation in hippocampal astrocytes and neurons (\u003Ca href=\"#B94\"\u003EWang et al., 2011\u003C\u002Fa\u003E). Similarly, hyperglycemic or acidified medium, as well as cytokines that stimulate epithelial-to-mesenchymal transition, increase mitochondrial transfer through tunneling nanotube formation (\u003Ca href=\"#B51\"\u003ELou et al., 2012\u003C\u002Fa\u003E). Therefore, stress can induce TNT formation, but further research is required to understand how TNT-mediated mitochondrial transfer is regulated. Notably, the protein S100A4 and its receptor guide the direction of nanotube growth (\u003Ca href=\"#B83\"\u003ESun et al., 2012\u003C\u002Fa\u003E). In stressed cells, p53 activates caspase-3 to cleave S100A4, creating a gradient in which the TNT initiating cell has the lower levels of the protein (\u003Ca href=\"#B83\"\u003ESun et al., 2012\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ch3\u003EExtracellular Vesicles\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EAlmost every cell type secretes a heterogeneous population of vesicles to the extracellular medium. This group of vesicles, ranging from 40 to 1000 nm, is referred to as extracellular vesicles (EVs). EVs can be divided into microvesicles, exosomes and apoptotic bodies, depending on their origin, size and molecular composition (Figure \u003Ca href=\"#F2\"\u003E2\u003C\u002Fa\u003E). EVs are vehicles of intercellular communication in a number physiological and pathological processes (\u003Ca href=\"#B55\"\u003EMittelbrunn and Sánchez-Madrid, 2012\u003C\u002Fa\u003E), and can be used as biomarkers of health and disease (\u003Ca href=\"#B69\"\u003EPitt et al., 2016\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F223255\u002Ffcell-04-00107-HTML\u002Fimage_m\u002Ffcell-04-00107-g002.jpg\" name=\"figure2\" target=\"_blank\"\u003E\r\n\u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F223255\u002Ffcell-04-00107-HTML\u002Fimage_t\u002Ffcell-04-00107-g002.gif\" id=\"F2\" alt=\"www.frontiersin.org\" \u002F\u003E\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 2. Loading of mitochondrial components in Extracellular Vesicles\u003C\u002Fstrong\u003E. Exosomes are small vesicles from 50 to 150 nm with an endocytic origin. The inward budding of late endosomes or multivesicular bodies (MVB) forms intraluminal vesicles that are released into the extracellular environment as exosomes through fusion of the MVB with the plasma membrane. Microvesicles, also called ectosomes, shed directly from plasma membrane and are very heterogeneous in size and composition. Apoptotic bodies are larger than 1 μm and are released by apoptotic cells that shed parts of their cytoplasm and organelles surrounded by plasma membrane (\u003Ca style=\"color:grey;\" href=\"#B55\"\u003EMittelbrunn and Sánchez-Madrid, 2012\u003C\u002Fa\u003E). Extracellular vesicles can contain mitochondrial fragments which include mitochondrial proteins and mtDNA (depicted in yellow and orange). Bigger particles can be loaded with full functional mitochondria (\u003Ca style=\"color:grey;\" href=\"#B68\"\u003EPhinney et al., 2015\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cp class=\"mb15 w100pc float_left mt15\"\u003EMitochondrial components have been detected in EVs, although the mechanisms by which mitochondrial proteins and mtDNA are loaded in the diverse EVs are still unknown. Exosomes, with a size ranging 40–150 nm, contain genetic material, mostly small RNAs (\u003Ca href=\"#B90\"\u003EVillarroya-Beltri et al., 2014\u003C\u002Fa\u003E), but genomic and mitochondrial DNA have also been detected (\u003Ca href=\"#B29\"\u003EGuescini et al., 2010a\u003C\u002Fa\u003E,\u003Ca href=\"#B30\"\u003Eb\u003C\u002Fa\u003E; \u003Ca href=\"#B40\"\u003EKahlert et al., 2014\u003C\u002Fa\u003E; \u003Ca href=\"#B85\"\u003EThakur et al., 2014\u003C\u002Fa\u003E). Larger EVs can contain entire mitochondrial particles and mtDNA, as observed in mesenchymal stem cells and astrocytes (\u003Ca href=\"#B68\"\u003EPhinney et al., 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B33\"\u003EHayakawa et al., 2016\u003C\u002Fa\u003E). These cells produce EVs with regenerative potential in several tissues under damaging conditions (\u003Ca href=\"#B43\"\u003EKhan et al., 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B59\"\u003ENakamura et al., 2015\u003C\u002Fa\u003E; \u003Ca href=\"#B63\"\u003EOng and Wu, 2015\u003C\u002Fa\u003E). Whether mitochondrial material contained in these vesicles participates in the regenerative potential of stem cells is yet to be shown.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EEVs participate in intercellular mitochondrial transfer (\u003Ca href=\"#B79\"\u003ESpees et al., 2006\u003C\u002Fa\u003E; \u003Ca href=\"#B37\"\u003EIslam et al., 2012\u003C\u002Fa\u003E; \u003Ca href=\"#B39\"\u003EJayaprakash et al., 2015\u003C\u002Fa\u003E). Horizontal transfer of mitochondria occurs through the transfer of either mitochondria-derived vesicles or intact mitochondria. To date, the mechanisms of intercellular transfer of free mtDNA across both mitochondrial inner and outer membranes and the plasma membrane remain elusive. Also, the transfer of whole mitochondrial particles is the most likely event mediating rescue of mitochondrial function through EVs during intercellular mitochondrial transfer, in which some cells would acquire a few mitochondria and replicate their mtDNA.\u003C\u002Fp\u003E\r\n\u003Ch3\u003ECell Fusion\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb15\"\u003ECell fusion is a process in which two independent cells fuse their membranes and share organelles and cytosolic compounds, while their nuclei remain intact. Permanent cell fusion result in cells that share the cytoplasm and possess unique karyotypes, while partial cell fusion allows transient, but direct, intercellular communication and exchange of multiple protein complexes and even subcellular organelles, including mitochondria. Fusion is a rare event in developed eukaryotic organisms, and a strict regulation of fusogen proteins and their receptors expression ensures that it only occurs under specific conditions (\u003Ca href=\"#B3\"\u003EAguilar et al., 2013\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EAdult and embryonic stem cells have been reported to fuse with cardiomyocytes, hepatocytes and neurons, which might contribute to the differentiation, plasticity, or maintenance of these cell types (\u003Ca href=\"#B6\"\u003EAlvarez-Dolado et al., 2003\u003C\u002Fa\u003E). Injury and inflammation may drive cell fusion in target organs. Cells from the myeloid and lymphoid lineage can fuse in low rates with different tissues in response to injury or inflammation (\u003Ca href=\"#B60\"\u003ENygren et al., 2008\u003C\u002Fa\u003E). Cell fusion improved regeneration in rodent livers that received bone marrow transplants (\u003Ca href=\"#B89\"\u003EVassilopoulos et al., 2003\u003C\u002Fa\u003E; \u003Ca href=\"#B93\"\u003EWang et al., 2003\u003C\u002Fa\u003E). Myocardial infarction also triggers fusion events between cardiomyocytes and bone marrow transplanted cells (\u003Ca href=\"#B61\"\u003EOh et al., 2003\u003C\u002Fa\u003E; Figure \u003Ca href=\"#F1\"\u003E1\u003C\u002Fa\u003E). Similarly, human MSC may fuse to small airway epithelial cells upon insult \u003Ci\u003Eex vivo\u003C\u002Fi\u003E (\u003Ca href=\"#B80\"\u003ESpees et al., 2003\u003C\u002Fa\u003E). However, to which extent mitochondrial transfer in these scenarios participates in the potential of stem cell fusion is unknown.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003ECell fusion can modify the potential of the cells involved, having important implications in regeneration and cancer (\u003Ca href=\"#B3\"\u003EAguilar et al., 2013\u003C\u002Fa\u003E). A major concern is whether fusion is physiologically relevant, since most studies used pluripotent or multipotent stem cells as at least one of the fusion partners. It is difficult to evaluate its actual impact in tissues, since cytokinesis may occur after fusion events, leaving new synkaryons that could be hardly distinguished from the rest of the cells in the tissue. This is the underlying reason why \u003Ci\u003Ein vivo\u003C\u002Fi\u003E reports of adult cell fusion are scarce, apart from those cells that form heterokaryons as part of their functional cycle, e.g., muscle, placenta or macrophages.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EOther Cellular Mechanisms\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EMitochondrial extrusion is another possible mechanism for mitochondrial transfer. It allows the release of mitochondria or mitochondrial components from cells under specific conditions. During tumor necrosis factor α-induced cell death, cytoplasmic vacuoles engulf mitochondria, which subsequently fuse with the plasma membrane, releasing free mitochondria to the extracellular medium (\u003Ca href=\"#B58\"\u003ENakajima et al., 2008\u003C\u002Fa\u003E). Likewise, LPS stimulation promotes the fusion of autophagolysosomes with the plasma membrane and the release of mitochondrial components that activate the inflammatory response (\u003Ca href=\"#B86\"\u003EUnuma et al., 2015\u003C\u002Fa\u003E). Neutrophils can extrude mitochondrial components, specifically oxidized mitochondrial nucleoids, which boost type I interferon secretion and can lead to the development of lupus (\u003Ca href=\"#B11\"\u003ECaielli et al., 2016\u003C\u002Fa\u003E). Under high rates of reactive oxygen species (ROS) HeLa cells can extrude fragments of mitochondria (\u003Ca href=\"#B52\"\u003ELyamzaev et al., 2008\u003C\u002Fa\u003E). Basophils release mtDNA in ROS dependent manner to create extracellular DNA traps to fight bacteria (\u003Ca href=\"#B56\"\u003EMorshed et al., 2014\u003C\u002Fa\u003E). Likewise, eosinophils rapidly release mtDNA in the extracellular space to bind and kill infectious bacteria (\u003Ca href=\"#B98\"\u003EYousefi et al., 2008\u003C\u002Fa\u003E). Mitochondrial extrusion not only occurs \u003Ci\u003Ein vitro\u003C\u002Fi\u003E, but also \u003Ci\u003Ein vivo\u003C\u002Fi\u003E. For example, platelets extrude functional mitochondria both encapsulated in microparticles and as free organelles. This way, they enhance inflammatory responses (\u003Ca href=\"#B8\"\u003EBoudreau et al., 2014\u003C\u002Fa\u003E). In addition, hepatocytes of mice treated with anti-Fas antibody extruded mitochondria, which were detected in the perisinusoidal space and in serum (\u003Ca href=\"#B58\"\u003ENakajima et al., 2008\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EFuture Perspectives and Therapeutic Opportunities\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EHorizontal mitochondrial transfer among cells occurs \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E. However, whether mitochondria move between cells under physiological conditions, and the precise role of this transfer remain unknown. Stem cells are likely organelle donors; thus, adult stem cells, mesenchymal stromal cells, fibroblasts, and hematopoietic stem cells, emerge as potential mitochondrial donors. These cells may transfer mitochondria to surrounding cells in their niche, thus affecting cell differentiation, proliferation, tissue homeostasis, development and aging. During the course of an immune response, immune cells show high capacity to exchange surface receptors and intercellular material (\u003Ca href=\"#B73\"\u003ERechavi et al., 2009\u003C\u002Fa\u003E). These cells can also extrude mitochondrial components under specific conditions (\u003Ca href=\"#B95\"\u003EWeinberg et al., 2015\u003C\u002Fa\u003E). Regarding the control of immune responses by those mechanisms, cognate immune cell-cell interactions such as immune synapses between lymphocytes and antigen-presenting cells, lymphocyte adhesion and migration across inflamed tissues or macrophage patrolling, may represent physiological scenarios in which mitochondrial intercellular exchange could control signaling, proliferation, bioenergetics or transcellular degradation of mitochondria. Professional phagocytic cells involved in inflammation and tissue regeneration may also acquire exogenous mitochondria (\u003Ca href=\"#B68\"\u003EPhinney et al., 2015\u003C\u002Fa\u003E), as it has been observed in the optic nerve head (\u003Ca href=\"#B18\"\u003EDavis et al., 2014\u003C\u002Fa\u003E). Notably, astrocytes transfer mitochondria to neurons supporting neuronal viability after ischaemic stroke (\u003Ca href=\"#B33\"\u003EHayakawa et al., 2016\u003C\u002Fa\u003E). Whether neurons and microglia crosstalk through intercellular mitochondrial transfer should be further addressed, in order to determine if defects on this type of communication are involved in pathogenesis and can represent a therapeutic target.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EUnraveling the physiological significance of mitochondrial transfer requires the development of novel fluorescence and genetic mitochondrial tracking tools. Many of the studies referred here use fluorescent dyes to track mitochondrial transfer, but the possibility of the leakage of these dyes is a limitation for this methodology. Visualizing intercellular organelle transfer in real time in the intact living organism remains a major methodological challenge. The use of available cells and mice with fluorescent proteins confined to mitochondria will greatly accelerate the progress in this field (\u003Ca href=\"#B1\"\u003EAbe et al., 2011\u003C\u002Fa\u003E; \u003Ca href=\"#B67\"\u003EPham et al., 2012\u003C\u002Fa\u003E). In addition, the use of mtDNA polymorphisms that allow the distinction of mtDNA from the donor and acceptor cells after mitochondria acquisition, the development of techniques to detect mitochondrial transfer (\u003Ca href=\"#B10\"\u003ECaicedo et al., 2015\u003C\u002Fa\u003E) and low levels of cell heteroplasmy in single cells from tissues, will help to unequivocally ascertain whether mitochondrial transfer occurs in the different scenarios. Importantly, the possible exchange of healthy mitochondria to sustain cells with OXPHOS deficiencies would prevent the manifestation of some diseases associated with mitochondrial dysfunction or with the heteroplasmic inheritance of mutated mtDNA. Hence, additional study is required to evaluate the real impact of these mechanisms in mitochondrial diseases.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EThe number of diseases in which impaired mitochondrial function is thought to contribute to pathogenesis is currently increasing. While the main strategy employed in the treatment of mitochondrial dysfunction involves targeting mitochondrial genes encoded by the nuclear genome, our current capacity to supplement, repair, or replace mitochondrial DNA in somatic cells is very limited (\u003Ca href=\"#B65\"\u003EPatananan et al., 2016\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EIdentification of the signaling pathways and the proteins controlling the transfer of mitochondria will improve its potential therapeutic application. Future therapeutic implications of this research need to consider strategies to pharmacologically enhance intercellular organelle transfer when desirable, or block its occurrence when it is deleterious, such as in the spread of infection or the maintenance of malignant cells. Given the considerable therapeutic potential of MSCs and mitochondrial transfer, future investigation of the mechanisms underlying the regulation of oxidative metabolism and dynamics of mitochondria in MSCs may ultimately facilitate the development of effective stem cell therapies for treatment of mitochondrial diseases. Elucidation of the mechanisms of mitochondrial transfer will help us create a potential cell therapy-based mitochondrial restoration or mitochondrial gene therapy for human diseases caused by mitochondrial dysfunction.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EAnother major concern pertains the required transfer dose. It might not be necessary to fully replace the mitochondria repertoire in the recipient cell to restore mitochondrial dysfunction. It is likely that the transfer of a low number of copies of a functional mtDNA could restore the normal copy number and therefore the mitochondrial function. Hence, tumors formed from cells with low copy number of mtDNA are able to recover them after injection into immunoincompetent mice (\u003Ca href=\"#B21\"\u003EDickinson et al., 2013\u003C\u002Fa\u003E). This would open a new field in which mitochondrial transfer therapy would be an option to treat injured tissues, taking into account that using healthy mitochondria from the same patient could lead to a better performance of the tissues because of the matching between mitochondrial and nuclear DNA (\u003Ca href=\"#B46\"\u003ELatorre-Pellicer et al., 2016\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EDT, FB, and FS: Elaboration and writing of the manuscript and making Figures. FS and FB contributed equally to this work.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest Statement\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EThe reviewer RG and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EWe thank Dr. Miguel Vicente-Manzanares and Carolina Villarroya-Beltri for their critical reading of the manuscript and editing. This study was supported by grants SAF2014-55579-R from the Spanish Ministry of Economy and Competitiveness, INDISNET-S2011\u002FBMD-2332 from the Comunidad de Madrid, ERC-2011-AdG 294340-GENTRIS, Red Cardiovascular RD 12-0042-0056 and grant PIE13\u002F00041 BIOIMID from Instituto Salud Carlos III (ISCIII). The Centro Nacional de Investigaciones Cardiovasculares (CNIC, Spain) is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\r\n\u003Cdiv class=\"References\"\u003E\r\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003E Abe, T., Kiyonari, H., Shioi, G., Inoue, K., Nakao, K., Aizawa, S., et al. (2011). 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Cell Dev. Biol.\u003C\u002Fi\u003E 4:107. doi: 10.3389\u002Ffcell.2016.00107\u003C\u002Fp\u003E\r\n\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 01 August 2016; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 14 September 2016;\u003Cbr\u002F\u003E \u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 28 September 2016.\u003C\u002Fp\u003E\r\n\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F112503\u002Foverview\"\u003EJennifer L. Stow\u003C\u002Fa\u003E, University of Queensland, Australia\u003C\u002Fdiv\u003E\r\n\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F36506\u002Foverview\"\u003EHilary Ann Coller\u003C\u002Fa\u003E, University of California, Los Angeles, USA\u003Cbr\u002F\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F163095\u002Foverview\"\u003EJames Alan Marrs\u003C\u002Fa\u003E, Indiana University – Purdue University Indianapolis, USA\u003Cbr\u002F\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F369318\u002Foverview\"\u003ERajesh Ghai\u003C\u002Fa\u003E, University of Queensland, Australia\u003C\u002Fdiv\u003E\r\n\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2016 Torralba, Baixauli and Sánchez-Madrid. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Francisco Sánchez-Madrid, \u003Ca href=\"mailto:fsmadrid@salud.madrid.org\"\u003Efsmadrid@salud.madrid.org\u003C\u002Fa\u003E\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Cspan\u003E\u003Csup\u003E†\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EThese authors have contributed equally to this work.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\r\n\r\n",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h3\"\u003EIntercellular Mitochondrial Transfer\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h4\"\u003ECellular Structures Mediating Intercellular Mitochondrial Transfer\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h5\"\u003EFuture Perspectives and Therapeutic Opportunities\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h6\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h7\"\u003EConflict of Interest Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h8\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h9\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n"},files:[{name:"EPUB.epub",fileServerPackageEntryId:g,type:{code:as,name:as}},{name:at,fileServerPackageEntryId:"fcell-04-00107\u002Ffcell-04-00107.pdf",type:{code:p,name:p}},{name:at,fileServerPackageEntryId:g,type:{code:p,name:p}},{name:"fcell-04-00107.xml",fileServerPackageEntryId:"fcell-04-00107\u002Ffcell-04-00107.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:g,type:{code:p,name:p}}]},currentArticlePageMetaInfo:{title:au,link:[{rel:"canonical",href:av}],meta:[{hid:w,property:w,name:w,content:aw},{hid:ax,property:ax,name:"title",content:au},{hid:ay,property:ay,name:w,content:aw},{hid:az,name:az,content:"horizontal genetic transfer,tunneling nanotubes,Mitochondrial Diseases,extracellular 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Cell Dev. Biol.","2296-634X",void 0,18,"Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares","Servicio de Inmunolog铆a, Instituto Investigaci贸n Sanitaria Princesa, Universidad Autonoma de Madrid","citation_author","citation_author_institution","Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares, Madrid, Spain",1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0A59C792-A2E1-415E-85D099C64C84D821\u002Fwebimage-A2D69EFA-B893-4809-9530D3B542ABEA2F.jpg","image","2022-06-27T09:59:04Z",2000,"fcell","journal_field","10.3389\u002Ffcell.2016.00107","Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer","\u003Cp\u003EMitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome encoding selected subunits of the oxidative phosphorylation complexes. Recent findings reveal that, in addition to being maternally inherited, mitochondria can traverse cell boundaries and thus be horizontally transferred between cells. Although, the physiological relevance of this phenomenon is still under debate, mitochondria uptake rescues mitochondrial respiration defects in recipient cells and regulates signaling, proliferation or chemotherapy resistance \u003Citalic\u003Ein vitro\u003C\u002Fitalic\u003E and \u003Citalic\u003Ein vivo\u003C\u002Fitalic\u003E. In this review, we outline the pathophysiological consequences of horizontal mitochondrial transfer and offer a perspective on the cellular and molecular mechanisms mediating their intercellular transmission, including tunneling nanotubes, extracellular vesicles, cellular fusion, and GAP junctions. The physiological relevance of mitochondrial transfer and the potential therapeutic application of this exchange for treating mitochondrial-related diseases are discussed.\u003C\u002Fp\u003E",374612,"Daniel",177508,"Francesc",17933,"Francisco",112503,"The University of Queensland","Australia",36506,"United States",163095,369318,"Rajesh",{},675,"Membrane Traffic and Organelle Dynamics","membrane-traffic-and-organelle-dynamics","EPUB","fcell-04-00107.pdf","Frontiers | Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fcell-and-developmental-biology\u002Farticles\u002F10.3389\u002Ffcell.2016.00107\u002Ffull","Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. 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