Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Volume 1757, Issue 5-6, Pages 567-572Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbabio.2006.05.015
Keywords
mitochondria; cancer; reactive oxygen species; succinate dehydrogenase
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HlF alpha prolyl hydroxylases (PHDs) are a family of enzymes that regulate protein levels of the a 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 hydroxyprolyl, carbon dioxide and succinate in a reaction dependent on ferrous iron and ascorbate as cofactors. Recently it was shown that pseudohypoxia, 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. (c) 2006 Elsevier B.V. All rights reserved.
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