Featured Research

from universities, journals, and other organizations

Nutrient-sensing enzymes key to starvation response and survival in newborn mammals

Date:
December 23, 2012
Source:
Whitehead Institute for Biomedical Research
Summary:
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. Researchers have now 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.

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 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 adaption."

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 been established in cultured cells by the Sabatini lab. Yet when Efeyan compared nutrient levels in fasting newborn RagA-active mice with those of fasting pups with normal RagA, not only amino acids were reduced in RagA-active animals, also glucose levels were dangerously low. The animals were unable to "sense" either of these reductions, so autophagy failed to initiate in the RagA-active pups, which all 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.


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. The original article was written by Nicole Giese Rura. Note: Materials may be edited for content and length.


Journal Reference:

  1. Alejo Efeyan, Roberto Zoncu, Steven Chang, Iwona Gumper, Harriet Snitkin, Rachel L. Wolfson, Oktay Kirak, David D. Sabatini, David M. Sabatini. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature, 2012; DOI: 10.1038/nature11745

Cite This Page:

Whitehead Institute for Biomedical Research. "Nutrient-sensing enzymes key to starvation response and survival in newborn mammals." ScienceDaily. ScienceDaily, 23 December 2012. <www.sciencedaily.com/releases/2012/12/121223152414.htm>.
Whitehead Institute for Biomedical Research. (2012, December 23). Nutrient-sensing enzymes key to starvation response and survival in newborn mammals. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2012/12/121223152414.htm
Whitehead Institute for Biomedical Research. "Nutrient-sensing enzymes key to starvation response and survival in newborn mammals." ScienceDaily. www.sciencedaily.com/releases/2012/12/121223152414.htm (accessed July 31, 2014).

Share This




More Plants & Animals News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Raw: Thousands Flocking to German Crop Circle

Raw: Thousands Flocking to German Crop Circle

AP (July 30, 2014) Thousands of people are trekking to a Bavarian farmer's field to check out a mysterious set of crop circles. (July 30) Video provided by AP
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins