Generation of reactive oxygen species by the mitochondrial electron transport chain.
Generation of reactive oxygen species (ROS) by the mitochondrial electron transport chain (ETC), which is composed of four multiprotein complexes named complex I-IV, is believed to be important in the aging process and in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Previous studies have identified the ubiquinone of complex III and an unknown component of complex I as the major sites of ROS generation. Here we show that the physiologically relevant ROS generation supported by the complex II substrate succinate occurs at the flavin mononucleotide group (FMN) of complex I through reversed electron transfer, not at the ubiquinone of complex III as commonly believed. Indirect evidence indicates that the unknown ROS-generating site within complex I is also likely to be the FMN group. It is therefore suggested that the major physiologically and pathologically relevant ROS-generating site in mitochondria is limited to the FMN group of complex I. These new insights clarify an elusive target for intervening mitochondrial ROS-related processes or diseases.
Liu
Yuanbin
Y
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037-9062, USA. liu@salk.edu
Fiskum
Gary
G
Schubert
David
D
D000375:Aging / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry; D004579:Electron Transport / Q000502:physiology*; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III / Q000737:chemistry / Q000378:metabolism; D005486:Flavin Mononucleotide / Q000737:chemistry / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism; D014451:Ubiquinone / Q000737:chemistry / Q000378:metabolism
D017382:Reactive Oxygen Species; D014451:Ubiquinone; D005486:Flavin Mononucleotide; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III