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.

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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


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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.

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  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.

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