title: Redox stress is not essential for the pseudo-hypoxic phenotype of succinate dehydrogenase deficient cells.
abstract: HIFalpha prolyl hydroxylases (PHDs) are a family of enzymes that regulate protein levels of the alpha subunit of the hypoxia inducible transcription factor (HIF) under different oxygen levels. PHDs catalyse the conversion of a prolyl residue, molecular oxygen and alpha-ketoglutarate to hydroxy-prolyl, carbon dioxide and succinate in a reaction dependent on ferrous iron and ascorbate as cofactors. Recently it was shown that pseudo-hypoxia, HIF induction under normoxic conditions, is an important feature of tumours generated as a consequence of inactivation of the mitochondrial tumour suppressor 'succinate dehydrogenase' (SDH). Two models have been proposed to describe the link between SDH inhibition and HIF activation. Both models suggest that a mitochondrial-generated signal leads to the inhibition of PHDs in the cytosol, however, the models differ in the nature of the proposed messenger. The first model postulates that mitochondrial-generated hydrogen peroxide mediates signal transduction while the second model implicates succinate as the molecular messenger which leaves the mitochondrion and inhibits PHDs in the cytosol. Here we show that pseudo-hypoxia can be observed in SDH-suppressed cells in the absence of oxidative stress and in the presence of effective antioxidant treatment.
authors.affiliation: Apoptosis and Tumour Physiology Laboratory, Cancer Research UK, Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland, UK.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Selak
authors.forename: Raul V
authors.initials: RV
authors.lastname: Durán
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D008954:Models, Biological; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013385:Succinate Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D000975:Antioxidants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D017382:Reactive Oxygen Species; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D013385:Succinate Dehydrogenase; D005978:Glutathione; D010100:Oxygen