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1Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5; 2Department of Molecular Biosciences, University of California, Davis, California 95616; and 3Department of Medicine, University of Wisconsin, Madison, Wisconsin 53606
Submitted 15 August 2003 ; accepted in final form 15 January 2004
Reductions in cellular oxygen consumption (
O2) and reactive oxygen species (ROS) production have been proposed as mechanisms underlying the anti-aging effects of calorie restriction (CR). Mitochondria are a cell's greatest "sink" for oxygen and also its primary source of ROS. The mitochondrial proton leak pathway is responsible for 20–30% of O2 in resting cells. We hypothesized that CR leads to decreased proton leak with consequential decreases in O2, ROS production, and cellular damage. Here, we report the effects of short-term (2-wk, 2-mo) and medium-term (6-mo) CR (40%) on rat muscle mitochondrial proton leak, ROS production, and whole animal O2. Whole body O2 decreased with CR at all time points, whereas mass-adjusted O2 was normal until the 6-mo time point, when it was 40% lower in CR compared with control rats. At all time points, maximal leak-dependent O2 was lower in CR rats compared with controls. Proton leak kinetics indicated that mechanisms of adaptation to CR were different between short- and medium-term treatments, with the former leading to decreases in protonmotive force (
p) and state 4 O2 and the latter to increases in p and decreases in state 4 O2. Results from metabolic control analyses of oxidative phosphorylation are consistent with the idea that short- and medium-term responses are distinct. Mitochondrial H2O2 production was lower in all three CR groups compared with controls. Overall, this study details the rapid effects of short- and medium-term CR on proton leak, ROS production, and metabolic control of oxidative phosphorylation. Results indicate that a reduction in mitochondrial O2 and ROS production may be a mechanism for the actions of CR.
aging; oxidative stress; oxidative phosphorylation; uncoupling protein
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