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Nutrient-sensing enzymes key to starvation response and survival in newborn mammals
Date:12/23/2012

CAMBRIDGE, Mass. (December 23, 2012) In the perilous hours immediately after birth, a newborn mammal must survive the sudden loss of food supply from its mother. Under normal circumstances, newborns mount a metabolic response to ward off starvation until feeding occurs. This survival response involves a process of controlled breakdown of internal energetic sources known as autophagy. Although autophagy has been well documented, the key mechanistic regulators of autophagy in vivo have remained poorly understood.

Whitehead Institute researchers have discovered that a family of nutrient-sensing enzymes, dubbed Rag GTPases, modulates the activity of the mTORC1 protein complex, whose inhibition is essential for autophagy and survival in newborns. The finding, reported this week in the journal Nature, emerges from the lab of Whitehead Member David Sabatini, whose earlier in vitro studies showed that mTORC1 (for "mechanistic target of rapamycin complex 1") senses the presence of vital amino acids via interactions with Rag GTPases.

To assess the impact of this Rag GTPase-mTORC1 relationship in mammals, the lab generated mice genetically altered to continually express an active form of the GTPase RagA and compared them with wild-type mice. In normal mice, RagA is activated in the presence of nutrients, and turns on the mTORC1 pathway, which regulates organismal growth in response to nutrient availability. If the mice are deprived of nutrients, RagA is switched off, deactivating mTORC1 and initiating autophagy to tide the animal over until the next feeding. However, in the altered mice, RagA's continuous activity keeps mTORC1 active, despite a dearth of available nutrients. Instead of mTORC1 triggering autophagy, the animals' metabolisms remain unchanged, resulting in nutritional crisis and death.

"What happens to a newborn animal with the RagA enzyme always on is pretty shocking," says Sabatini, who is also a professor of biology at
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Contact: Nicole Rura
rura@wi.mit.edu
617-258-6851
Whitehead Institute for Biomedical Research
Source:Eurekalert

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