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

Am J Physiol Endocrinol Metab. 2004 May;286(5):E852-61. doi: 10.1152/ajpendo.00367.2003. Epub 2004 Jan 21.


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 (Deltap) and state 4 Vo2 and the latter to increases in Deltap 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.

Publication types

  • Comparative Study

MeSH terms

  • Analysis of Variance
  • Animals
  • Body Weight / physiology
  • Caloric Restriction*
  • Carrier Proteins / metabolism
  • Energy Metabolism / physiology*
  • Hydrogen Peroxide / metabolism
  • Ion Channels
  • Kinetics
  • Male
  • Mitochondria, Muscle / metabolism*
  • Mitochondrial Proteins
  • Muscle, Skeletal / metabolism*
  • Nutritional Status / physiology
  • Oxidation-Reduction
  • Oxygen Consumption / physiology
  • Phosphorylation
  • Proton Pumps / metabolism
  • Protons*
  • Rats
  • Rats, Inbred F344
  • Reactive Oxygen Species / metabolism*
  • Time Factors
  • Uncoupling Protein 3


  • Carrier Proteins
  • Ion Channels
  • Mitochondrial Proteins
  • Proton Pumps
  • Protons
  • Reactive Oxygen Species
  • Uncoupling Protein 3
  • Hydrogen Peroxide