title: Production of endogenous matrix superoxide from mitochondrial complex I leads to activation of uncoupling protein 3.
abstract: Superoxide generated using exogenous xanthine oxidase indirectly activates an uncoupling protein (UCP)-mediated proton conductance of the mitochondrial inner membrane. We investigated whether endogenous mitochondrial superoxide production could also activate proton conductance. When respiring on succinate, rat skeletal muscle mitochondria produced large amounts of matrix superoxide. Addition of GDP to inhibit UCP3 markedly inhibited proton conductance and increased superoxide production. Both superoxide production and the GDP-sensitive proton conductance were suppressed by rotenone plus an antioxidant. Thus, endogenous superoxide can activate the proton conductance of UCP3, which in turn limits mitochondrial superoxide production. These observations provide a departure point for studies under more physiological conditions.
authors.affiliation: MRC Dunn Human Nutrition Unit, Hills Road, CB2 2XY, Cambridge, UK.
authors.forename: Darren A
authors.initials: DA
authors.lastname: Talbot
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Lambert
authors.forename: Martin D
authors.initials: MD
authors.lastname: Brand
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000032:analysis / Q000378:metabolism; D007473:Ion Channels; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024101:Mitochondrial Proteins; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D019802:Succinic Acid / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000071247:Uncoupling Protein 3; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011522:Protons; C000604392:UCP3 protein, human; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D012402:Rotenone; D013481:Superoxides; D014810:Vitamin E; D006153:Guanosine Diphosphate; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I