Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1 alpha during Hypoxia: a mechanism of O sub(2) sensing

During hypoxia, hypoxia-inducible factor-1 alpha (HIF-1 alpha ) is required for induction of a variety of genes including erythropoietin and vascular endothelial growth factor. Hypoxia increases mitochondrial reactive oxygen species (ROS) generation at Complex III, which causes accumulation of HIF-1...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-08, Vol.275 (33), p.25130-25138
Main Authors: Chandel, N S, McClintock, D S, Feliciano, CE, Wood, T M, Melendez, JA, Rodriguez, A M, Schumacker, P T
Format: Article
Language:English
Subjects:
hypoxia-inducible factor-1^a
hypoxia-inducible factor-1a
Paracoccus denitrificans
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Summary:During hypoxia, hypoxia-inducible factor-1 alpha (HIF-1 alpha ) is required for induction of a variety of genes including erythropoietin and vascular endothelial growth factor. Hypoxia increases mitochondrial reactive oxygen species (ROS) generation at Complex III, which causes accumulation of HIF-1 alpha protein responsible for initiating expression of a luciferase reporter construct under the control of a hypoxic response element. This response is lost in cells depleted of mitochondrial DNA ( rho super(0) cells). Overexpression of catalase abolishes hypoxic response element-luciferase expression during hypoxia. Exogenous H sub(2)O sub(2) stabilizes HIF-1 alpha protein during normoxia and activates luciferase expression in wild-type and rho super(0) cells. Isolated mitochondria increase ROS generation during hypoxia, as does the bacterium Paracoccus denitrificans. These findings reveal that mitochondria-derived ROS are both required and sufficient to initiate HIF-1 alpha stabilization during hypoxia.
ISSN:0021-9258
1083-351X