The role of autophagy during the early neonatal starvation period

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.

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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.

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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.

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Correspondence to Noboru Mizushima.

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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)

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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

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