title: Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production.
abstract: Mitochondria are a major source of superoxide, formed by the one-electron reduction of oxygen during electron transport. Superoxide initiates oxidative damage to phospholipids, proteins and nucleic acids. This damage may be a major cause of degenerative disease and aging. In isolated mitochondria, superoxide production on the matrix side of the membrane is particularly high during reversed electron transport to complex I driven by oxidation of succinate or glycerol 3-phosphate. Reversed electron transport and superoxide production from complex I are very sensitive to proton motive force, and can be strongly decreased by mild uncoupling of oxidative phosphorylation. Both matrix superoxide and the lipid peroxidation product 4-hydroxy-trans-2-nonenal can activate uncoupling through endogenous UCPs (uncoupling proteins). We suggest that superoxide releases iron from aconitase, leading to a cascade of lipid peroxidation and the release of molecules such as hydroxy-nonenal that covalently modify and activate the proton conductance of UCPs and other proteins. A function of the UCPs may be to cause mild uncoupling in response to matrix superoxide and other oxidants, leading to lowered proton motive force and decreased superoxide production. This simple feedback loop would constitute a self-limiting cycle to protect against excessive superoxide production, leading to protection against aging, but at the cost of a small elevation of respiration and basal metabolic rate.
authors.affiliation: MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K. martin.brand@mrc-dunn.cam.ac.uk
authors.forename: Martin D
authors.initials: MD
authors.lastname: Brand
authors.forename: Julie A
authors.initials: JA
authors.lastname: Buckingham
authors.forename: Telma C
authors.initials: TC
authors.lastname: Esteves
authors.forename: Katherine
authors.initials: K
authors.lastname: Green
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Lambert
authors.forename: Satomi
authors.initials: S
authors.lastname: Miwa
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Julian L
authors.initials: JL
authors.lastname: Pakay
authors.forename: Darren A
authors.initials: DA
authors.lastname: Talbot
authors.forename: Karim S
authors.initials: KS
authors.lastname: Echtay
mesh_terms: D000375:Aging; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D000071256:Uncoupling Protein 1; D013481:Superoxides