title: Mitochondrial Ca2+ homeostasis in human NADH:ubiquinone oxidoreductase deficiency.
abstract: NADH:ubiquinone oxidoreductase or complex I is a large multisubunit assembly of the mitochondrial inner membrane that channels high-energy electrons from metabolic NADH into the electron transport chain (ETC). Its dysfunction is associated with a range of progressive neurological disorders, often characterized by a very early onset and short devastating course. To better understand the cytopathological mechanisms of these disorders, we use live cell luminometry and imaging microscopy of patient skin fibroblasts with mutations in nuclear-encoded subunits of the complex. Here, we present an overview of our recent work, showing that mitochondrial membrane potential, Ca(2+) handling and ATP production are to a variable extent impaired among a large cohort of patient fibroblast lines. From the results obtained, the picture emerges that a reduction in cellular complex I activity leads to a depolarization of the mitochondrial membrane potential, resulting in a decreased supply of mitochondrial ATP to the Ca(2+)-ATPases of the intracellular stores and thus to a reduced Ca(2+) content of these stores. As a consequence, the increase in cytosolic Ca(2+) concentration evoked by a Ca(2+) mobilizing stimulus is decreased, leading to a reduction in mitochondrial Ca(2+) accumulation and ensuing ATP production and thus to a hampered energization of stimulus-induced cytosolic processes.
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. p.willems@ncmis.ru.nl
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
authors.forename: Federica
authors.initials: F
authors.lastname: Valsecchi
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Verkaart
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Visch
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D042967:Electron Transport Complex I / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D028361:Mitochondrial Diseases / Q000209:etiology; D009154:Mutation; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013841:Thiazepines / Q000494:pharmacology
chemical_list: C106746:1,5-benzothiazepine; D020746:Calcium Channels, L-Type; D013841:Thiazepines; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D000252:Calcium-Transporting ATPases; D002118:Calcium