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Biochim Biophys Acta. 2011 Jul;1813(7):1263-8. doi: 10.1016/j.bbamcr.2010.08.006. Epub 2010 Aug 21.

Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning.

Author information

  • Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. gsemenza@jhmi.edu

Abstract

Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability by regulating gene expression. A critical cell-autonomous adaptive response to chronic hypoxia controlled by HIF-1 is reduced mitochondrial mass and/or metabolism. Exposure of HIF-1-deficient fibroblasts to chronic hypoxia results in cell death due to excessive levels of reactive oxygen species (ROS). HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV; induction of pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; induction of BNIP3, which triggers mitochondrial selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters that are required for oxidative phosphorylation. HIF-1 is also required for ischemic preconditioning and this effect may be due in part to its induction of CD73, the enzyme that produces adenosine. HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

Copyright © 2010 Elsevier B.V. All rights reserved.

PMID:
20732359
[PubMed - indexed for MEDLINE]
PMCID:
PMC3010308
Free PMC Article

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