The role of autophagy during the early neonatal starvation period : Abstract : Nature

Nature 432, 1032-1036 (23 December 2004) | doi:10.1038/nature03029; Received 10 August 2004; Accepted 17 September 2004; Published online 3 November 2004

The role of autophagy during the early neonatal starvation period

Akiko Kuma^1,^2,^5,⁷, Masahiko Hatano^2,⁴, Makoto Matsui^5,^6,⁷, Akitsugu Yamamoto⁸, Haruaki Nakaya³, Tamotsu Yoshimori⁹, Yoshinori Ohsumi^5,⁶, Takeshi Tokuhisa² and Noboru Mizushima^1,^5,⁷

Time's Arrow and Biosignaling, PRESTO, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
Department of Developmental Genetics (H2), Chiba University, Chiba 260-8670, Japan
Department of Pharmacology (F2), Chiba University Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Biomedical Research Center, Chiba University, Chiba 260-8670, Japan
Department of Cell Biology, National Institute for Basic Biology, he Graduate University for Advanced Studies, Okazaki 444-8585, Japan
Department of Molecular Biomechanics, School of Life Science, the Graduate University for Advanced Studies, Okazaki 444-8585, Japan
Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan
Department of Cell Genetics, National Institute of Genetics, Mishima 411-8540, Japan

Correspondence to: Noboru Mizushima^1,^5,⁷ Email: nmizu@rinshoken.or.jp

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 lysosomes^2,^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 ( $approx$ 12 h) is much shorter than that of wild-type mice ( $approx$ 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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