title: The molecular basis by which dietary restricted feeding reduces mitochondrial reactive oxygen species generation.
abstract: Restricted feeding regimes in rodents that extend longevity lower the rate of mitochondrial reactive oxygen species generation. This effect is not dependent upon the depression of the state III and IV mitochondrial respiration rates. Mitochondria from liver, skeletal muscle and brown adipose tissue adapt to DR feeding with a lowered membrane potential that results from an enhanced proton leak across the inner membrane. Mitochondrial ROS generation is very sensitive to the magnitude of the membrane potential and the enhanced proton leak and ROS generation rates are reversible by exogenous insulin in liver and heart mitochondria. The adenine nucleotide translocase (ANT) was shown to be the dominant proton leak channel induced under DR feeding regimes in these tissues, while in brown fat mitochondria, UCP1 was activated, but this was not sensitive to exogenous insulin treatment. The effect of DR to modify the proton leak, membrane potential and ROS generation rate can be simulated by a range of non-esterified free fatty acids (NEFA) acting on the ANT to enhance its protonophoric activity. Mobilisation of NEFA under DR feeding, when insulin plasma concentrations are extremely low, explains the indirect action of insulin to counteract the effects of DR feeding on mitochondrial ROS generation.
authors.affiliation: School of Biological Sciences, University of Liverpool, Liverpool, L67 7ZB, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Ash
authors.forename: B J
authors.initials: BJ
authors.lastname: Merry
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D010101:Oxygen Consumption; D018892:Proton-Motive Force; D051381:Rats; D011914:Rats, Inbred BN; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D005934:Glucagon; D000226:Mitochondrial ADP, ATP Translocases; D006861:Hydrogen Peroxide