Editors' ChoiceMetabolism

Surviving Birth

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Science Signaling  05 Feb 2013:
Vol. 6, Issue 261, pp. ec33
DOI: 10.1126/scisignal.2004026

A profound change that occurs with birth is the transition from the maternally supplied nutrients delivered through the placenta to the necessity for feeding and metabolic regulation by the neonate. The mechanistic target of rapamycin complex 1 (mTORC1) is a critical regulator of cellular metabolism, activated by both amino acids [through the guanosine triphosphatases (GTPases) RagA, B, C, and D] and growth factors (through the GTPases TSC1 and TSC2), and requires sufficient glucose or energy stores [through AMP-activated protein kinase (AMPK)]. Amino acids stimulate the formation of Rag-GTP, which recruits mTORC1 to the lysosomal surface for activation. Efeyan et al. engineered mice in which RagA was constitutively active (RagAGTP) and found that, although the mice developed normally in utero and were born at Mendelian ratios, the pups failed to survive and died within a day of birth. Tissues from wild-type RagA pups showed inhibition of mTORC1 activity within 1 hour of fasting, whereas tissues from the RagAGTP pups did not. Inhibition of mTOR with rapamycin prolonged the survival of the RagAGTP pups. The hypoglycemia that occurred after birth persisted in the RagAGTP pups and was not due to defective use of glycogen, which was more rapidly depleted in these mice compared with the wild-type mice. Instead, the RagAGTP pups had reduced circulating amino acids, and injection of gluconeogenic amino acids delayed death. Electron microscopic analysis and biochemical experiments indicated that the RagAGTP pups were deficient in autophagy and lysosomal biogenesis. Because activity of mTORC1 is inhibited under conditions of low glucose through the AMPK pathway, it was unexpected that mTORC1 activity would remain high in the RagAGTP pups during extreme hypoglycemia. Studies with cultured mouse embryo fibroblasts or transfected human embryonic kidney–293 cells suggested that mTORC1 was resistant to inhibition by low glucose when the RagAGTP was present. Glucose failed to stimulate the release of mTORC1 from the lysosome in the RagAGTP-expressing cells. Thus, Rag GTPases appear to function in both amino acid– and glucose-mediated regulation of mTORC1 activity. Immediately after birth, inhibition of mTORC1 in response to hypoglycemia is necessary to trigger induction of autophagy to supply the amino acids needed to sustain plasma glucose concentrations.

A. Efeyan, R. Zoncu, S. Chang, I. Gumper, H. Snitkin, R. L. Wolfson, O. Kirak, D. D. Sabatini, D. M. Sabatini, Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–683 (2013). [PubMed]