The role of autophagy during the early neonatal starvation period

Nature volume 432, pages1032–1036(2004)Cite this article

Abstract

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 options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

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.

References

  1. 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. 2

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

    Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

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

    Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 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)

    CAS  Article  Google Scholar 

  8. 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)

    CAS  Article  Google Scholar 

  9. 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)

    CAS  Article  Google Scholar 

  10. 10

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

    ADS  CAS  Article  Google Scholar 

  11. 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)

    CAS  Article  Google Scholar 

  12. 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)

    CAS  Article  Google Scholar 

  13. 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)

    ADS  CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 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)

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 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)

    CAS  Article  Google Scholar 

  18. 18

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

    ADS  CAS  Article  Google Scholar 

  19. 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)

    CAS  Article  Google Scholar 

  20. 20

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

    ADS  CAS  Article  Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  23. 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)

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 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)

    CAS  Article  Google Scholar 

  27. 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)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

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

Affiliations

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

    Akiko Kuma & Noboru Mizushima

  2. Department of Developmental Genetics (H2), Chiba University, 260-8670, Chiba, Japan

    Akiko Kuma, Masahiko Hatano & Takeshi Tokuhisa

  3. Department of Pharmacology (F2), Chiba University Graduate School of Medicine, Chiba University, 260-8670, Chiba, Japan

    Haruaki Nakaya

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

    Masahiko Hatano

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

    Akiko Kuma, Makoto Matsui, Yoshinori Ohsumi & Noboru Mizushima

  6. Department of Molecular Biomechanics, School of Life Science, the Graduate University for Advanced Studies, 444-8585, Okazaki, Japan

    Makoto Matsui & Yoshinori Ohsumi

  7. Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, 113-8613, Tokyo, 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

Authors
  1. Akiko Kuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masahiko Hatano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Makoto Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akitsugu Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haruaki Nakaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tamotsu Yoshimori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshinori Ohsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takeshi Tokuhisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Noboru Mizushima
    View author publications

    You can also search for this author in PubMed Google Scholar

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). https://doi.org/10.1038/nature03029

Download citation

Further reading

Comments

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.

Search

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