Letter | Published:

The role of autophagy during the early neonatal starvation period

Nature volume 432, pages 10321036 (23 December 2004) | Download Citation



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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , & in Perinatal Biochemistry (eds Herrera, E. & Knopp, R.) 233–258 (CRC Press, Boca Raton, 1992)

  2. 2.

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

  3. 3.

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

  4. 4.

    , & Autophagosome formation in mammalian cells. Cell Struct. Funct. 27, 421–429 (2002)

  5. 5.

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

  6. 6.

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

  7. 7.

    , , , & Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum. J. Biol. Chem. 278, 17636–17645 (2003)

  8. 8.

    , , , & The Drosophila homolog of Aut1 is essential for autophagy and development. FEBS Lett. 543, 154–158 (2003)

  9. 9.

    , & Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004)

  10. 10.

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

  11. 11.

    , , , & The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana. J. Biol. Chem. 277, 33105–33114 (2002)

  12. 12.

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

  13. 13.

    , , , & Beclin1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003)

  14. 14.

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

  15. 15.

    , , , & 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)

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

    , , & 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)

  22. 22.

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

  23. 23.

    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)

  24. 24.

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

  25. 25.

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

  26. 26.

    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)

  27. 27.

    , , , & Non-injection methods for the production of embryonic stem cell-embryo chimaeras. Nature 365, 87–89 (1993)

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


  1. Time's Arrow and Biosignaling, PRESTO, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

    • Akiko Kuma
    •  & Noboru Mizushima
  2. Department of Developmental Genetics (H2), Chiba University, Chiba 260-8670, Japan

    • Akiko Kuma
    • , Masahiko Hatano
    •  & Takeshi Tokuhisa
  3. Department of Pharmacology (F2), Chiba University Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

    • Haruaki Nakaya
  4. Biomedical Research Center, Chiba University, Chiba 260-8670, Japan

    • Masahiko Hatano
  5. Department of Cell Biology, National Institute for Basic Biology, he Graduate University for Advanced Studies, Okazaki 444-8585, Japan

    • Akiko Kuma
    • , Makoto Matsui
    • , Yoshinori Ohsumi
    •  & Noboru Mizushima
  6. Department of Molecular Biomechanics, School of Life Science, the Graduate University for Advanced Studies, Okazaki 444-8585, Japan

    • Makoto Matsui
    •  & Yoshinori Ohsumi
  7. Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan

    • Akiko Kuma
    • , Makoto Matsui
    •  & Noboru Mizushima
  8. Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan

    • Akitsugu Yamamoto
  9. Department of Cell Genetics, National Institute of Genetics, Mishima 411-8540, Japan

    • Tamotsu Yoshimori


  1. Search for Akiko Kuma in:

  2. Search for Masahiko Hatano in:

  3. Search for Makoto Matsui in:

  4. Search for Akitsugu Yamamoto in:

  5. Search for Haruaki Nakaya in:

  6. Search for Tamotsu Yoshimori in:

  7. Search for Yoshinori Ohsumi in:

  8. Search for Takeshi Tokuhisa in:

  9. Search for Noboru Mizushima in:

Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Noboru Mizushima.

Supplementary information

Image files

  1. 1.

    Supplementary Figure S1

    Representative histological sections of haematoxylin and eosin-stained brain from wild type and Atg5-/- newborns.

  2. 2.

    Supplementary Figure S2

    The restriction map of the wild-type Atg5 allele, the targeting construct, and the mutated allele.

Word documents

  1. 1.

    Supplementary Figure Legends

  2. 2.

    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.

About this article

Publication history






Further reading


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.