Hypoxia-inducible factor 1: Regulator of mitochondrial metabolism and mediator of ischemic preconditioning |
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| Authors: | Gregg L. Semenza |
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| Affiliation: | Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA |
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| 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. |
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| Keywords: | Electron transport chain Heart Myocardial Oxygen Reactive oxygen species Respiration |
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