Reactive oxygen species generated at mitochondrial Complex III stabilize hypoxia-inducible factor-1α during hypoxia: A mechanism of O2 sensing

N. S. Chandel, D. S. McClintock, C. E. Feliciano, T. M. Wood, J. A. Melendez, A. M. Rodriguez, P. T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticle

1319 Scopus citations

Abstract

During hypoxia, hypoxia-inducible factor-1α (HIF-1α) 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-1α 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 (p0 cells). Overexpression of catalase abolishes hypoxic response element-luciferase expression during hypoxia. Exogenous H2O2 stabilizes HIF-1α protein during normoxia and activates luciferase expression in wild-type and p0 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-1α stabilization during hypoxia.

Original languageEnglish (US)
Pages (from-to)25130-25138
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number33
DOIs
StatePublished - Aug 18 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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