title: Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production.
abstract: 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.
authors.affiliation: Dept. of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Univ. of Ottawa, Ottawa, ON, Canada K1H 8M5.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bevilacqua
authors.forename: Jon J
authors.initials: JJ
authors.lastname: Ramsey
authors.forename: Kevork
authors.initials: K
authors.lastname: Hagopian
authors.forename: Richard
authors.initials: R
authors.lastname: Weindruch
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000502:physiology; D031204:Caloric Restriction; D002352:Carrier Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels; D007700:Kinetics; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D009752:Nutritional Status / Q000502:physiology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D010766:Phosphorylation; D017494:Proton Pumps / Q000378:metabolism; D011522:Protons; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017494:Proton Pumps; D011522:Protons; D017382:Reactive Oxygen Species; D000071247:Uncoupling Protein 3; D006861:Hydrogen Peroxide