Mitochondria regulate cell stress

Mitochondrial energy stores allow cells to survive when stressed, and offer clues on how calorie restriction increases lifespan

By | September 20, 2007

Mitochondria play an unexpectedly important role in cell survival in the face of stress, according to a paper in this week's Cell. The authors suggest that this cell stress response may provide clues about how calorie restriction extends lifespan in mammals. "The physiology of the mitochondria is critical for determining whether a cell lives or dies," said senior author David Sinclair of Harvard Medical School. The study shows that "cells have a very neat mechanism to try to maintain mitochondrial [energy] levels," said Shin-ichiro Imai of Washington University in St. Louis, who wasn't involved in the research. "This is important to prevent cells from [undergoing] apoptosis." Previous work has shown a connection between cellular death, organism longevity, and NAD+ (nicotinamide adenine dinucleotide), a molecule required for many metabolic processes. Severe genotoxic stress leads to loss of NAD+, which induces cell death. Recent studies have shown that cells may respond to mild stress, including calorie restriction, by increasing NAD+ synthesis. Calorie restriction also induces expression of genes called sirtuins, which extend lifespan in many species. Many of the connections between stress, cell death, and lifespan have been made in yeast. To see if similar pathways are at work in mammals, the researchers studied the effects of a protein called Nampt, which synthesizes NAD+. They found that overexpressing this protein protected cells against chemical stressors, as expected. Surprisingly, however, these cells still suffered depletion of NAD+. Somehow, the NAD+ synthesizing protein was keeping cells alive, while NAD+ levels themselves plummeted. This result "was a complete shock," Sinclair said. The researchers found a possible explanation when they examined the link between the NAD+ pathway and sirtuins. Levels of NAD+ were not tied to SIRT1, the sirtuin associated with lifespan extension in mammals. Instead, two other sirtuins -- SIRT3 and SIRT4 -- were required for cell survival in response to chemical stress. Crucially, these sirtuins are only expressed in mitochondria. The authors then used a novel mass spectrometry technique to measure NAD+ concentration specifically in mitochondria. Unlike in the cell nucleus and cytoplasm, NAD+ levels in mitochondria remained stable when cells were chemically stressed -- showing that mitochondrial metabolism, but not whole-cell metabolism, keeps cells running when they're stressed. "As long as the mitochondria are physiologically active, the cell can otherwise be depleted of energy, but it stays alive," Sinclair said. No one has been able to measure mitochondrial NAD+ levels before, according to Frédéric Picard of Laval University in Québec, who was not involved in the work. Developing a new mass spectrometry technique allowed the researchers to make this measurement for the first time, Sinclair told The Scientist. Finally, the researchers found that mitochondrial energy stores are responsive to changes in diet. The liver cells of rats that fasted for 48 hours showed increased mitochondrial NAD+ levels, which could underlie superior cell survival and therefore longevity, the authors suggest. The study is the first to link mitochondrial sirtuins to stress resistance in the cell, and the first to link sirtuins other than SIRT1 to caloric restriction, Sinclair said. He added that molecules in the mitochondrial NAD+ pathway may represent new drug targets to treat diseases of aging. Sinclair co-founded the company Sirtris Pharmaceuticals in Cambridge, Mass., to develop drugs based on sirtuin pathways to treat age-related disease. Showing that cells prevent death by maintaining a stable supply of NAD+ in mitochondria is "a very novel finding," Imai told The Scientist. However, "a 48-hour fast is not calorie restriction," warned Picard. "It's quite a stretch to say that one is related to the other." It's reasonable to speculate that mitochondrial NAD+ effects are related to longevity, since cell survival is related to aging, he said, but more work will be required to make definitive ties to calorie restriction. "I would rather reserve my opinion about a possible connection to aging," Imai agreed. "Stress response is a very important part in aging, but we need to see definitive proof. That's definitely the next interesting step." Melissa Lee Phillips Links within this article: H. Yang et al., "Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival," Cell, September 21, 2007. David Sinclair Shin-ichiro Imai A. Burkle, "Poly(ADP-ribose). The most elaborate metabolite of NAD+," The FEBS Journal, September 2005. J.R. Revollo et al., "The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells," Journal of Biological Chemistry, December 3, 2004. M.W. Anderson, "Sir2: scrambling for answers," The Scientist, December 6, 2004. L. Guarente, F. Picard, "Calorie restriction--the SIR2 connection," Cell, February 25, 2005. K.R. Chi, "What is visfatin?" The Scientist, June 26, 2007. A. Rongvaux et al., "Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis," European Journal of Immunology, November, 2002. G. Flores, "Fast track to longevity," The Scientist, March 7, 2005. Frédéric Picard Sirtris Pharmaceuticals


September 21, 2007

The news is a pointer towards what may lie underneath the observations about caloric restriction and stress to living at cellular level. Many of the connections and explanations between stress, caloric restriction, and lifespan have been made in past. The research to find out pathways continues, though. The present news is a romantic one! The link between the NAD+ pathway, sirtuins. and presumed increase in lifespan are to be elaborated further. The sirtuins may be crucially important in this context.\n

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