Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation.
Virtually every mammalian cell contains mitochondria. These double-membrane organelles continuously change shape and position and contain the complete metabolic machinery for the oxidative conversion of pyruvate, fatty acids, and amino acids into ATP. Mitochondria are crucially involved in cellular Ca2+ and redox homeostasis and apoptosis induction. Maintenance of mitochondrial function and integrity requires an inside-negative potential difference across the mitochondrial inner membrane. This potential is sustained by the electron-transport chain (ETC). NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest protein complex of the ETC, couples the oxidation of NADH to the reduction of ubiquinone. During this process, electrons can escape from CI and react with ambient oxygen to produce superoxide and derived reactive oxygen species (ROS). Depending on the balance between their production and removal by antioxidant systems, ROS may function as signaling molecules or induce damage to a variety of biomolecules or both. The latter ultimately leads to a loss of mitochondrial and cellular function and integrity. In this review, we discuss (a) the role of CI in mitochondrial functioning; (b) the composition, structure, and biogenesis of CI; (c) regulation of CI function; (d) the role of CI in ROS generation; and (e) adaptive responses to CI deficiency.
Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. w.koopman@ncmls.ru.nl
Werner J H
WJ
Koopman
Leo G J
LG
Nijtmans
Cindy E J
CE
Dieteren
Peggy
P
Roestenberg
Federica
F
Valsecchi
Jan A M
JA
Smeitink
Peter H G M
PH
Willems
D000818:Animals; D001692:Biological Transport; D002417:Cattle; D002839:Chromans / Q000494:pharmacology; D004579:Electron Transport / Q000502:physiology; D042967:Electron Transport Complex I / Q000172:deficiency / Q000502:physiology*; D005057:Eukaryotic Cells / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D008322:Mammals / Q000378:metabolism*; D008563:Membrane Lipids / Q000502:physiology; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000502:physiology; D009245:NADH Dehydrogenase / Q000502:physiology; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
D002839:Chromans; D008563:Membrane Lipids; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D012402:Rotenone; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid