title: Superoxide production is inversely related to complex I activity in inherited complex I deficiency.
abstract: Deficiency of NADH:ubiquinone oxidoreductase or complex I (CI) is the most common cause of disorders of the oxidative phosphorylation system in humans. Using life cell imaging and blue-native electrophoresis we quantitatively compared superoxide production and CI amount and activity in cultured skin fibroblasts of 7 healthy control subjects and 21 children with inherited isolated CI deficiency. Thirteen children had a disease causing mutation in one of the nuclear-encoded CI subunits, whereas in the remainder the genetic cause of the disease is not yet established. Superoxide production was significantly increased in all but two of the patient cell lines. An inverse relationship with the amount and residual activity of CI was observed. In agreement with this finding, rotenone, a potent inhibitor of CI activity, dose-dependently increased superoxide production in healthy control cells. Also in this case an inverse relationship with the residual activity of CI was observed. In sharp contrast, however, rotenone did not decrease the amount of CI. The data presented show that superoxide production is increased in inherited CI deficiency and that this increase is primarily a consequence of the reduction in cellular CI activity and not of a further leakage of electrons from mutationally malformed complexes.
authors.affiliation: Department of Membrane Biochemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Verkaart
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Sjenet E
authors.initials: SE
authors.lastname: van Emst-de Vries
authors.forename: Leo G J
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Lambertus W P J
authors.initials: LW
authors.lastname: van den Heuvel
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: D002675:Child, Preschool; D042967:Electron Transport Complex I / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D012402:Rotenone / Q000008:administration & dosage; D012867:Skin / Q000201:enzymology; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*; D014475:Uncoupling Agents / Q000008:administration & dosage
chemical_list: D014475:Uncoupling Agents; D012402:Rotenone; D013481:Superoxides; D042967:Electron Transport Complex I