title: The antioxidant Trolox restores mitochondrial membrane potential and Ca2+ -stimulated ATP production in human complex I deficiency.
abstract: Malfunction of mitochondrial complex I caused by nuclear gene mutations causes early-onset neurodegenerative diseases. Previous work using cultured fibroblasts of complex-I-deficient patients revealed elevated levels of reactive oxygen species (ROS) and reductions in both total Ca(2+) content of the endoplasmic reticulum (ER(Ca)) and bradykinin(Bk)-induced increases in cytosolic and mitochondrial free Ca(2+) ([Ca(2+)](C); [Ca(2+)](M)) and ATP ([ATP](C); [ATP](M)) concentration. Here, we determined the mitochondrial membrane potential (Delta psi) in patient skin fibroblasts and show significant correlations with cellular ROS levels and ER(Ca), i.e., the less negative Delta psi, the higher these levels and the lower ER(Ca). Treatment with 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox) normalized Delta psi and Bk-induced increases in [Ca(2+)](M) and [ATP](M). These effects were accompanied by an increase in ER(Ca) and Bk-induced increase in [Ca(2+)](C). Together, these results provide evidence for an integral role of increased ROS levels in complex I deficiency and point to the potential therapeutic value of antioxidant treatment.
authors.affiliation: Department of Biochemistry (286), Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Visch
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000172:deficiency*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002839:Chromans; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D001920:Bradykinin; D002118:Calcium