title: Adrenodoxin (Adx) and CYP11A1 (P450scc) induce apoptosis by the generation of reactive oxygen species in mitochondria.
abstract: Mitochondrial cytochrome P450 systems are an indispensable component of mammalian steroid biosynthesis; they catalyze regio- and stereo-specific steroid hydroxylations and consist of three protein entities: adrenodoxin reductase (AdR), adrenodoxin (Adx), and a mitochondrial cytochrome P450 enzyme, e.g., CYP11A1 (P450 side chain cleavage, P450scc). It is known that the latter two are able to generate reactive oxygen species (ROS) in vitro . In this study, we investigated whether this ROS generation also occurs in vivo and, if so, whether it leads to the induction of apoptosis. We found that overexpression of either human or bovine Adx causes a significant loss of viability in 11 different cell lines. This loss of viability does not depend on the presence of the tumor suppressor protein p53. Transient overexpression of human Adx in HCT116 cells leads to ROS production, to a disruption of the mitochondrial transmembrane potential (DeltaPsi), to cytochrome c release from the mitochondria, and to caspase activation. In contrast, the effect of transient overexpression of human CYP11A1 on cell viability varies in different cell lines, with some being sensitive and others not. We conclude that mitochondrial cytochrome P450 systems are a source of mitochondrial ROS production and can play a role in the induction of mitochondrial apoptosis.
authors.affiliation: Department of Biochemistry, Building No. 9.2, Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Derouet-Hümbert
authors.forename: Klaus
authors.initials: K
authors.lastname: Roemer
authors.forename: Matthias
authors.initials: M
authors.lastname: Bureik
mesh_terms: D000325:Adrenodoxin / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000325:Adrenodoxin; D045304:Cytochromes c; D002786:Cholesterol Side-Chain Cleavage Enzyme; D020169:Caspases