title: Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?
abstract: Malfunction of NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest complex of the mitochondrial oxidative phosphorylation system, has been implicated in a wide variety of human disorders. To demonstrate a quantitative relationship between CI amount and activity and mitochondrial shape and cellular reactive oxygen species (ROS) levels, we recently combined native electrophoresis and confocal and video microscopy of dermal fibroblasts of healthy control subjects and children with isolated CI deficiency. Individual mitochondria appeared fragmented and/or less branched in patient fibroblasts with a severely reduced CI amount and activity (class I), whereas patient cells in which these latter parameters were only moderately reduced displayed a normal mitochondrial morphology (class II). Moreover, cellular ROS levels were significantly more increased in class I compared with class II cells. We propose a mechanism in which a mutation-induced decrease in the cellular amount and activity of CI leads to enhanced ROS levels, which, in turn, induce mitochondrial fragmentation when not appropriately counterbalanced by the cell's antioxidant defense systems.
authors.affiliation: Department of Membrane Biochemistry, Radboud University Nijmegen Medical Centre, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands.
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Verkaart
authors.forename: Henk Jan
authors.initials: HJ
authors.lastname: Visch
authors.forename: Sjenet
authors.initials: S
authors.lastname: van Emst-de Vries
authors.forename: Leo G J
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
mesh_terms: D002460:Cell Line; D002648:Child; D016000:Cluster Analysis; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D053142:Mitochondrial Size; D009154:Mutation; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015203:Reproducibility of Results; D012402:Rotenone / Q000494:pharmacology; D012720:Severity of Illness Index; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D042967:Electron Transport Complex I