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1 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
2 Department of Molecular Biosciences, University of California, Davis, CA, USA
3 Department of Medicine, University of Wisconsin, Madison, WI, USA
* To whom correspondence should be addressed. E-mail: mharper{at}uottawa.ca.
Reductions in cellular oxygen consumption 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 consumption in resting cells. We hypothesized that CR leads to decreased
proton leak with consequential decreases in O2 consumption, ROS production, and
cellular damage. Here we report the effects of short- (2 weeks; 2 months) and medium-
(6 months) term CR (40%) on rat muscle mitochondrial proton leak, ROS production,
and whole animal oxygen consumption. Whole body O2 consumption decreased with CR
at all time points, while mass-adjusted O2 consumption was normal until the 6 mo time
point where it was 40% lower in CR compared to control rats. At all time points,
maximal leak-dependent O2 consumption was lower in CR rats compared to 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 consumption, and the latter to increases in p and
decreases in state 4 O2 consumption. 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 to controls. Overall, this study details the rapid effects of short- and medium-term
CR on proton leak, ROS production and on metabolic control of oxidative
phosphorylation. Results indicate that a reduction in mitochondrial O2 consumption and
ROS production may be a mechanism for the actions of CR.
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