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December 25, 2012--------News Archive Return to: News Alerts

Autophagy is a survival response involving the controlled breakdown
of internal energy sources in nutrient-deprived cells.

(Left, top and bottom)
To determine if the enzyme RagA plays a role in triggering autophagy, a protein
involved in autophagy has been tagged green in these embryonic mouse skin cells.

In the cells with normal RagA activity, the protein clusters together after the
cells are starved of amino acids, indicating that the cells have initiated autophagy.

(Right, top and bottom)
In cells with RagA always active, the protein remains distributed throughout
the cells, showing that autophagy has not started despite the cells' starved state.

Image: Courtesy of Nature

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Nutrient-Sensing Enzymes Key to Survival in Newborns

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 energy
sources known as autophagy.

Although autophagy has been well documented, the key mechanistic regulators of autophagy in vivo have remained poorly understood. Now, Whitehead Institute researchers have discovered that a family of nutrient-sensing enzymes, dubbed Rag GTPases, modify the activity of the mTORC1 protein complex – essential for autophagy and survival in newborns.

The finding, reported this week in the journal Nature, is from the lab of David Sabatini, whose earlier 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 Rag GTPase-mTORC1 in mammals, the lab generated mice genetically altered to continually express GTPase RagA, and compared them with wild-type (normal) mice. In normal mice, RagA is activated by nutrients, turning on the mTORC1 pathway which regulates the embryo's growth in response to nutrient availability.

If a newborn mouse is deprived of nutrients, the enzyme
RagA is switched off, deactivating the mTORC1 pathway
and initiating autophagy (the controlled breakdown of
cellular energy sources) to tide the animal
over until its' next feeding.

However, in the altered mice, RagA is continuously
switched on keeping mTORC1 active despite a lack
of available cellular nutrients.

Instead of mTORC1 triggering autophagy,
the animals' metabolisms remains 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 MIT and a Howard Hughes Medical Institute (HHMI) investigator. "A normal neonate animal within an hour after birth responds to that condition, but one with its RagA stuck 'on' doesn't, and it dies. It basically has a huge energetic and nutritional crisis because it can't make the adaptation."

These striking results stunned Alejo Efeyan, a postdoctoral researcher in the Sabatini lab, and first author of the Nature that describes this work.

"We were surprised that there was no inhibition of this pathway independent of RagA—that there is no backup system," says Efeyan. "And that RagA is a more global nutrient sensor that goes beyond its known function as an amino acid sensor."

RagA's role as an amino acid sensor had previously been
established in cultured cells by the Sabatini lab.

Yet when Efeyan compared nutrient levels in fasting
newborn RagA-active mice to those of fasting pups with
normal RagA levels, in RagA-active pups amino acids
were reduced and glucose levels were dangerously low.

The RagA-active pups were unable to "sense" either of
the reduced amino acid and glucose levels, so autophagy
failed to initiate and all pups died within hours of birth.

This newly identified function for RagA suggests much remains unknown about the cell biology of nutrient sensing, an area of research that Sabatini and his lab continue to investigate.

This work was supported by National Institutes of Health (R01CA129105, R01 CA103866 and R37 AI047389), the American Federation for Aging, Starr Foundation, Koch Institute Frontier Research Program, the Ellison Medical Foundation, the Human Frontiers Science Program, the Jane Coffin Childs Memorial Fund for Medical Research, and the LAM Foundation.

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Full Citation:
"Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival"

Nature, online on December 23, 2012.

Alejo Efeyan (1,2,3,4,5), Roberto Zoncu (1,2,3,4,5), Steven Chang (1,2,3,4,5), Iwona Gumper (6), Harriet Snitkin (6), Rachel L. Wolfson (1,2,3,4,5), Oktay Kirak (1,7), David D. Sabatini (6) and David M. Sabatini (1,2,3,4,5).

1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.

2. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.

3. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

4. David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

5. Howard Hughes Medical Institute, MIT, Cambridge, MA, 02139.

6. Department of Cell Biology, New York University School of Medicine, New York, NY 10016-6497, USA.

7. Present address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.

Original article: http://wi.mit.edu/news/archive/2012/nutrient-sensing-enzymes-key-starvation-response-and-survival-newborn-mammals