Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The role of autophagy during the early neonatal starvation period


At birth the trans-placental nutrient supply is suddenly interrupted, and neonates face severe starvation until supply can be restored through milk nutrients1. 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Autophagy is upregulated during the early postnatal period in wild-type mice.
Figure 2: Generation of Atg5-/- mice.
Figure 3: Early postnatal lethality of Atg5-/- mice.
Figure 4: The energy depleted status of Atg5-/- mice.


  1. Medina, J. M., Vicario, C., Juanes, M. & Fernandez, E. in Perinatal Biochemistry (eds Herrera, E. & Knopp, R.) 233–258 (CRC Press, Boca Raton, 1992)

    Google Scholar 

  2. Cuervo, A. M. Autophagy: in sickness and in health. Trends Cell Biol. 14, 70–77 (2004)

    Article  Google Scholar 

  3. Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004)

    Article  CAS  Google Scholar 

  4. Mizushima, N., Ohsumi, Y. & Yoshimori, T. Autophagosome formation in mammalian cells. Cell Struct. Funct. 27, 421–429 (2002)

    Article  Google Scholar 

  5. Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003)

    Article  CAS  Google Scholar 

  6. Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993)

    Article  CAS  Google Scholar 

  7. Otto, G. P., Wu, M. Y., Kazgan, N., Anderson, O. R. & Kessin, R. H. Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum. J. Biol. Chem. 278, 17636–17645 (2003)

    Article  CAS  Google Scholar 

  8. Juhasz, G., Csikos, G., Sinka, R., Erdelyi, M. & Sass, M. The Drosophila homolog of Aut1 is essential for autophagy and development. FEBS Lett. 543, 154–158 (2003)

    Article  CAS  Google Scholar 

  9. Scott, R. C., Schuldiner, O. & Neufeld, T. P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004)

    Article  CAS  Google Scholar 

  10. Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003)

    Article  ADS  CAS  Google Scholar 

  11. Doelling, J. H., Walker, J. M., Friedman, E. M., Thompson, A. R. & Veirstra, R. D. The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana. J. Biol. Chem. 277, 33105–33114 (2002)

    Article  CAS  Google Scholar 

  12. Hanaoka, H. et al. Leaf senescence and starvation-induced chlorosis are accelerated by the disruption of an Arabidopsis autophagy gene. Plant Physiol. 129, 1181–1193 (2002)

    Article  CAS  Google Scholar 

  13. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003)

    Article  ADS  CAS  Google Scholar 

  14. Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003)

    Article  CAS  Google Scholar 

  15. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004)

    Article  CAS  Google Scholar 

  16. Mizushima, N. Methods for monitoring autophagy. Int. J. Biochem. Cell Biol. 36, 2491–2502 (2004)

    Article  CAS  Google Scholar 

  17. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000)

    Article  CAS  Google Scholar 

  18. Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488–492 (2000)

    Article  ADS  CAS  Google Scholar 

  19. Kabeya, Y. et al. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J. Cell Sci. 117, 2805–2812 (2004)

    Article  CAS  Google Scholar 

  20. Mizushima, N. et al. A protein conjugation system essential for autophagy. Nature 395, 395–398 (1998)

    Article  ADS  CAS  Google Scholar 

  21. Mizushima, N., Sugita, H., Yoshimori, T. & Ohsumi, Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 273, 33889–33892 (1998)

    Article  CAS  Google Scholar 

  22. Mizushima, N. et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol. 152, 657–667 (2001)

    Article  CAS  Google Scholar 

  23. Brun, S. et al. Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. Diabetes 48, 1217–1222 (1999)

    Article  CAS  Google Scholar 

  24. Hardie, D. G. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144, 5179–5183 (2003)

    Article  CAS  Google Scholar 

  25. Carling, D. The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem. Sci. 29, 18–24 (2004)

    Article  CAS  Google Scholar 

  26. Yamamoto, A. et al. Stacks of flattened smooth endoplasmic reticulum highly enriched in inositol 1,4,5-trisphosphate (InsP3) receptor in mouse cerebellar Purkinje cells. Cell Struct. Funct. 16, 419–432 (1991)

    Article  CAS  Google Scholar 

  27. Wood, S. A., Allen, N. D., Rossant, J., Auerbach, A. & Nagy, A. Non-injection methods for the production of embryonic stem cell-embryo chimaeras. Nature 365, 87–89 (1993)

    Article  ADS  CAS  Google Scholar 

Download references


We thank M. 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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Noboru Mizushima.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

Representative histological sections of haematoxylin and eosin-stained brain from wild type and Atg5-/- newborns. (JPG 64 kb)

Supplementary Figure S2

The restriction map of the wild-type Atg5 allele, the targeting construct, and the mutated allele. (JPG 23 kb)

Supplementary Figure Legends (DOC 20 kb)

Supplementary Table

Plasma and tissue amino acid concentrations in newborn mice under fasting conditions at 0 h and at 10 h after the caesarean delivery under fasting condition. (DOC 30 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kuma, A., Hatano, M., Matsui, M. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing