Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production

Lisa Bevilacqua, Jon J Ramsey, Kevork Hagopian, Richard Weindruch, Mary Ellen Harper

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


Reductions in cellular oxygen consumption (Vo2) 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 Vo2 in resting cells. We hypothesized that CR leads to decreased proton leak with consequential decreases in Vo2, 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 Vo2. Whole body Vo2 decreased with CR at all time points, whereas mass-adjusted Vo2 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 Vo2 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 (Δp) and state 4 Vo 2 and the latter to increases in Δp and decreases in state 4 Vo2. 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 Vo2 and ROS production may be a mechanism for the actions of CR.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5 49-5
StatePublished - May 2004


  • Aging
  • Oxidative phosphorylation
  • Oxidative stress
  • Uncoupling protein

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry


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