title: The production of reactive oxygen species by complex I.
abstract: ROS (reactive oxygen species) are considered to be a major cause of cellular oxidative stress, linked to neuromuscular diseases and aging. Complex I (NADH:ubiquinone oxidoreductase) is one of the main contributors to superoxide production by mitochondria, and knowledge of its mechanism of O2 reduction is required for the formulation of causative connections between complex I defects and pathological effects. There is evidence for two distinct (but not mutually exclusive) sites of O2 reduction by complex I. Studies of the isolated enzyme largely support the participation of the reduced flavin mononucleotide in the active site for NADH oxidation, and this mechanism is supported in mitochondria by correlations between the NAD(P)+ potential and O2 reduction. In addition, studies of intact mitochondria or submitochondrial particles have suggested a mechanism involving the quinone-binding site, supported by observations during reverse electron transport and the use of 'Q-site' inhibitors. Here, we discuss extant data and models for O2 reduction by complex I. We compare results from the isolated enzyme with results from intact mitochondria, aiming to identify similarities and differences between them and progress towards combining them to form a single, unified picture.
authors.affiliation: Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK. jh@mrc-dunn.cam.ac.uk
authors.forename: Judy
authors.initials: J
authors.lastname: Hirst
authors.forename: Martin S
authors.initials: MS
authors.lastname: King
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Pryde
mesh_terms: D001665:Binding Sites; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005415:Flavins / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D005415:Flavins; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I; D010100:Oxygen