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PMID: 10833514 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing.

The Journal of biological chemistry ·Vol. 275 ·No. 33 ·2000-08-18 ·Pages 25130-8

Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT

Abstract

During hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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(0) cells). Overexpression of catalase abolishes hypoxic response element-luciferase expression during hypoxia. Exogenous H(2)O(2) stabilizes HIF-1alpha protein during normoxia and activates luciferase expression in wild-type and rho(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-1alpha stabilization during hypoxia.

MeSH Terms

Androstadienes/pharmacology Animals Cell Line Cell Nucleus/metabolism Chelating Agents/pharmacology Cobalt/pharmacology Cytosol/chemistry DNA-Binding Proteins/metabolism Deferoxamine/pharmacology Dose-Response Relationship, Drug Electron Transport Complex III/chemistry,metabolism Electron Transport Complex IV/metabolism Enzyme Inhibitors/pharmacology Genes, Reporter Humans Hydrogen Peroxide/metabolism Hypoxia Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Immunoblotting Marine Toxins Mitochondria/enzymology,metabolism Mitochondria, Liver/metabolism Models, Biological Nuclear Proteins/metabolism Oxazoles/pharmacology Oxidation-Reduction Oxygen/metabolism Paracoccus denitrificans/metabolism Rats Reactive Oxygen Species/metabolism Time Factors Transcription Factors Transfection Tumor Cells, Cultured Wortmannin

Chemicals

Androstadienes Chelating Agents DNA-Binding Proteins Enzyme Inhibitors HIF1A protein, human Hif1a protein, rat Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Marine Toxins Nuclear Proteins Oxazoles Reactive Oxygen Species Transcription Factors Cobalt calyculin A Hydrogen Peroxide Electron Transport Complex IV Electron Transport Complex III cobaltous chloride Deferoxamine Oxygen Wortmannin

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Chandel N S

Department of Medicine, The University of Chicago, IL 60637, USA.

McClintock D S

Feliciano C E

Wood T M

Melendez J A

Rodriguez A M

Schumacker P T

Article Info

Journal

The Journal of biological chemistry

Abbr.

J Biol Chem

ISSN

0021-9258

DOI

10.1074/jbc.M001914200

Published

2000-08-18

Pages

25130-8

Language

English

Region

United States

NLM ID

2985121R

Subset

Grants

NHLBI NIH HHS · HL32646 · United States

NHLBI NIH HHS · HL35440 · United States

External Links

PubMed source DOI: 10.1074/jbc.M001914200 View journal details

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Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing.

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