title: Uncoupling to survive? The role of mitochondrial inefficiency in ageing.
abstract: Mitochondria are incompletely coupled, and during oxidative phosphorylation some of the redox energy in substrates is lost as heat. Incomplete coupling is mostly due to a natural leak of protons across the mitochondrial inner membrane. In rat hepatocytes the futile cycle of proton pumping and proton leak is responsible for 20-25% of respiration; in perfused rat muscle the value is 35-50%. Mitochondrial proton cycling is estimated to cause 20-25% of basal metabolic rate in rats. Proton cycling is equally prominent in hepatocytes from several different mammalian and ectotherm species, so it may be a general pathway of ecologically significant energy loss in all aerobes. Because it occurs in ectotherms, thermogenesis cannot be its primary function. Instead, an attractive candidate for the function of the universal and expensive energy-dissipating proton cycle is to decrease the production of superoxide and other reactive oxygen species (ROS). This could be important in helping to minimise oxidative damage to DNA and in slowing ageing. Mitochondria are the major source of cellular ROS, and increased mitochondrial proton conductance leads to oxidation of ubiquinone and decreased ROS production in isolated mitochondria. However, to date there is no direct evidence in cells or organisms that mitochondrial proton cycling lowers ROS production or oxidative damage or that it increases lifespan.
authors.affiliation: MRC Dunn Human Nutrition Unit, Hills Road, CB2 2XY, Cambridge, UK. martin.brand@mrc-dunn.cam.ac.uk
authors.forename: M D
authors.initials: MD
authors.lastname: Brand
mesh_terms: D000375:Aging; D000818:Animals; D005075:Biological Evolution; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D010085:Oxidative Phosphorylation; D018892:Proton-Motive Force; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species