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A more recent version of this article appeared on April 14, 2006
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M511626200v1
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Papers In Press, published online ahead of print February 14, 2006
J. Biol. Chem, 10.1074/jbc.M511626200
Submitted on October 26, 2005
Revised on February 7, 2006
Accepted on February 14, 2006

The mammalian longevity-assoiciated gene product p66shc regulates mitochondrial metabolism

Shino Nemoto, Christian A. Combs, Stephanie French, Bong-Hyun Ahn, Maria M. Fergusson, Robert S. Balaban, and Toren Finkel

NIH-NHLBI-LMB, NIH, Bethesda, MD 20892

Corresponding Author: finkelt{at}nih.gov

Previous studies have determined that mice with a homozygous deletion in the adapter protein p66shc have an extended life span and that cells derived from these mice exhibit lower levels of reactive oxygen species. Here we demonstrate that a fraction of p66shc localizes to the mitochondria and that p66shc -/- fibroblasts have altered mitochondrial energetics. In particular, despite similar cytochrome content, under basal conditions, the oxygen consumption of spontaneously immortalized p66shc -/- mouse embryonic fibroblasts were lower than similarly maintained wild type cells. Differences in oxygen consumption were particularly evident under chemically uncoupled conditions demonstrating that p66shc -/- cells have a reduction in both their resting and maximal oxidative capacity. We further demonstrate that reconstitution of p66shc expression in p66shc-/- cells increases oxygen consumption. The observed defect in oxidative capacity seen in p66shc -/- cells is partially offset by augmented levels of aerobic glycolysis. This metabolic switch is manifested by p66shc -/- cells exhibiting an increase in lactate production and a stricter requirement for extracellular glucose in order to maintain intracellular ATP levels. In addition, using an in vivo NADH photobleaching technique, we demonstrate that mitochondrial NADH metabolism is reduced in p66shc-/- cells. These results demonstrate that p66shc regulates mitochondrial oxidative capacity and suggest that p66shc may extend lifespan by repartitioning metabolic energy conversion away from oxidative and towards glycolytic pathways.


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