The role of autophagy during the early neonatal starvation period

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Here, we show that neonates adapt to this adverse circumstance by inducing autophagy. Autophagy is the primary means for the degradation of cytoplasmic constituents within lysosomes2,3,4. The level of autophagy in mice remains low during embryogenesis; however, autophagy is immediately upregulated in various tissues after birth and is maintained at high levels for 3–12 h before returning to basal levels within 1–2 days. Mice deficient for Atg5, which is essential for autophagosome formation, appear almost normal at birth but die within 1 day of delivery. The survival time of starved Atg5-deficient neonates (∼ 12 h) is much shorter than that of wild-type mice (∼ 21 h) but can be prolonged by forced milk feeding. Atg5-deficient neonates exhibit reduced amino acid concentrations in plasma and tissues, and display signs of energy depletion. These results suggest that the production of amino acids by autophagic degradation of ‘self’ proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.","datePublished":"2004-11-03T00:00:00Z","dateModified":"2004-11-03T00:00:00Z","pageStart":"1032","pageEnd":"1036","sameAs":"https://doi.org/10.1038/nature03029","keywords":["Science","Humanities and Social 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class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Akiko-Kuma-Aff1-Aff2-Aff5-Aff7" data-author-popup="auth-Akiko-Kuma-Aff1-Aff2-Aff5-Aff7" data-author-search="Kuma, Akiko">Akiko Kuma</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff5">5</a>,<a href="#Aff7">7</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Masahiko-Hatano-Aff2-Aff4" data-author-popup="auth-Masahiko-Hatano-Aff2-Aff4" data-author-search="Hatano, Masahiko">Masahiko Hatano</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Makoto-Matsui-Aff5-Aff6-Aff7" data-author-popup="auth-Makoto-Matsui-Aff5-Aff6-Aff7" data-author-search="Matsui, Makoto">Makoto Matsui</a><sup class="u-js-hide"><a href="#Aff5">5</a>,<a href="#Aff6">6</a>,<a href="#Aff7">7</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Akitsugu-Yamamoto-Aff8" data-author-popup="auth-Akitsugu-Yamamoto-Aff8" data-author-search="Yamamoto, Akitsugu">Akitsugu Yamamoto</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Haruaki-Nakaya-Aff3" data-author-popup="auth-Haruaki-Nakaya-Aff3" data-author-search="Nakaya, Haruaki">Haruaki Nakaya</a><sup class="u-js-hide"><a 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class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">25k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">29 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nature03029/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>At birth the trans-placental nutrient supply is suddenly interrupted, and neonates face severe starvation until supply can be restored through milk nutrients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Medina, J. M., Vicario, C., Juanes, M. & Fernandez, E. in Perinatal Biochemistry (eds Herrera, E. & Knopp, R.) 233–258 (CRC Press, Boca Raton, 1992)" href="/articles/nature03029#ref-CR1" id="ref-link-section-d504355532e514">1</a></sup>. Here, we show that neonates adapt to this adverse circumstance by inducing autophagy. Autophagy is the primary means for the degradation of cytoplasmic constituents within lysosomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Cuervo, A. M. Autophagy: in sickness and in health. Trends Cell Biol. 14, 70–77 (2004)" href="/articles/nature03029#ref-CR2" id="ref-link-section-d504355532e518">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004)" href="/articles/nature03029#ref-CR3" id="ref-link-section-d504355532e521">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Mizushima, N., Ohsumi, Y. & Yoshimori, T. Autophagosome formation in mammalian cells. Cell Struct. Funct. 27, 421–429 (2002)" href="/articles/nature03029#ref-CR4" id="ref-link-section-d504355532e524">4</a></sup>. The level of autophagy in mice remains low during embryogenesis; however, autophagy is immediately upregulated in various tissues after birth and is maintained at high levels for 3–12 h before returning to basal levels within 1–2 days. Mice deficient for <i>Atg5</i>, which is essential for autophagosome formation, appear almost normal at birth but die within 1 day of delivery. The survival time of starved <i>Atg5</i>-deficient neonates (<span class="stix">∼</span> 12 h) is much shorter than that of wild-type mice (<span class="stix">∼</span> 21 h) but can be prolonged by forced milk feeding. <i>Atg5</i>-deficient neonates exhibit reduced amino acid concentrations in plasma and tissues, and display signs of energy depletion. These results suggest that the production of amino acids by autophagic degradation of ‘self’ proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.</p></div></div></section> <noscript> <div class="c-nature-box c-nature-box--side " data-component="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fnature03029" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or subscribe</span> </a> </div> </div> </noscript> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> 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Miwa and H. Satake for technical assistance. We also thank S. Sugano for donation of the pEF321-T plasmid; K. Ono and K. Tanaka for histological examination of the brain; M. Tamagawa for instruction in electrocardiogram recording; and S. Nishio, N. Tsunekawa and M. Terai for discussions. Amino acid measurements were carried out with the aid of the Center for Analytical Instruments at the National Institute for Basic Biology. This work was supported in part by Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Time's Arrow and Biosignaling, PRESTO, Japan Science and Technology Agency, 332-0012, Kawaguchi, Japan</p><p class="c-article-author-affiliation__authors-list">Akiko Kuma & Noboru Mizushima</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Developmental Genetics (H2), Chiba University, 260-8670, Chiba, Japan</p><p class="c-article-author-affiliation__authors-list">Akiko Kuma, Masahiko Hatano & Takeshi Tokuhisa</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Pharmacology (F2), Chiba University Graduate School of Medicine, Chiba University, 260-8670, Chiba, Japan</p><p class="c-article-author-affiliation__authors-list">Haruaki Nakaya</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Biomedical Research Center, Chiba University, 260-8670, Chiba, Japan</p><p class="c-article-author-affiliation__authors-list">Masahiko Hatano</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Department of Cell Biology, National Institute for Basic Biology, he Graduate University for Advanced Studies, 444-8585, Okazaki, Japan</p><p class="c-article-author-affiliation__authors-list">Akiko Kuma, Makoto Matsui, Yoshinori Ohsumi & Noboru Mizushima</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department of Molecular Biomechanics, School of Life Science, the Graduate University for Advanced Studies, 444-8585, Okazaki, Japan</p><p class="c-article-author-affiliation__authors-list">Makoto Matsui & Yoshinori Ohsumi</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, 113-8613, Tokyo, Japan</p><p class="c-article-author-affiliation__authors-list">Akiko Kuma, Makoto Matsui & Noboru Mizushima</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, 526-0829, Japan</p><p class="c-article-author-affiliation__authors-list">Akitsugu Yamamoto</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Cell Genetics, National Institute of Genetics, Mishima, 411-8540, Japan</p><p class="c-article-author-affiliation__authors-list">Tamotsu Yoshimori</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Akiko-Kuma-Aff1-Aff2-Aff5-Aff7"><span class="c-article-authors-search__title u-h3 js-search-name">Akiko Kuma</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Akiko%20Kuma" class="c-article-button" data-track="click" data-track-action="author link - 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