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.
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March 2004
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Conference Article|
March 01 2004
Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production
Martin D. Brand;
Martin D. Brand
1
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
1To whom correspondence should be addressed (e-mail [email protected]).
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Julie A. Buckingham;
Julie A. Buckingham
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Telma C. Esteves;
Telma C. Esteves
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Katherine Green;
Katherine Green
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Adrian J. Lambert;
Adrian J. Lambert
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Satomi Miwa;
Satomi Miwa
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Michael P. Murphy;
Michael P. Murphy
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Julian L. Pakay;
Julian L. Pakay
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Darren A. Talbot;
Darren A. Talbot
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Karim S. Echtay
Karim S. Echtay
1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, U.K.
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Publisher: Portland Press Ltd
Online ISSN: 1744-1439
Print ISSN: 0067-8694
© 2004 The Biochemical Society
2004
Biochem Soc Symp (2004) 71: 203–213.
Citation
Chris Cooper, Mike Wilson, Victor Darley-Usmar, Martin D. Brand, Julie A. Buckingham, Telma C. Esteves, Katherine Green, Adrian J. Lambert, Satomi Miwa, Michael P. Murphy, Julian L. Pakay, Darren A. Talbot, Karim S. Echtay; Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production. Biochem Soc Symp 1 March 2004; 71 203–213. doi: https://doi.org/10.1042/bss0710203
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