title: Mitochondrial respiratory chain complex I is inactivated by NADPH oxidase Nox4.
abstract: ROS (reactive oxygen species) generated by NADPH oxidases play an important role in cellular signal transduction regulating cell proliferation, survival and differentiation. Nox4 (NADPH oxidase 4) induces cellular senescence in human endothelial cells; however, intracellular targets for Nox4 remained elusive. In the present study, we show that Nox4 induces mitochondrial dysfunction in human endothelial cells. Nox4 depletion induced alterations in mitochondrial morphology, stabilized mitochondrial membrane potential and decreased production of H(2)O(2) in mitochondria. High-resolution respirometry in permeabilized cells combined with native PAGE demonstrated that Nox4 specifically inhibits the activity of mitochondrial electron transport chain complex I, and this was associated with a decreased concentration of complex I subunits. These data suggest a new pathway by which sustained Nox4 activity decreases mitochondrial function.
authors.affiliation: Institute for Biomedical Aging Research, Innsbruck University, Rennweg 10, 6020 Innsbruck, Austria.
authors.forename: Rafał
authors.initials: R
authors.lastname: Kozieł
authors.forename: Haymo
authors.initials: H
authors.lastname: Pircher
authors.forename: Manuela
authors.initials: M
authors.lastname: Kratochwil
authors.forename: Barbara
authors.initials: B
authors.lastname: Lener
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Norbert A
authors.initials: NA
authors.lastname: Dencher
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
mesh_terms: D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000737:chemistry* / Q000172:deficiency / Q000502:physiology*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology
chemical_list: D021122:Protein Subunits; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D042967:Electron Transport Complex I