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

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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.

Research Highlights

► Hypoxia-inducible factor 1 (HIF-1) maintains oxygen homeostasis by directly activating transcription of target genes and by indirectly repressing gene expression through the transactivation of genes encoding transcriptional repressors and microRNAs. ► Within each cell, O2 supply and utilization must be optimized in order to prevent the production of excess reactive oxygen species, which can cause oxidative damage to cellular DNA, proteins, and lipids. HIF-1 regulates the balance between oxidative and glycolytic metabolism by directly activating transcription of target genes encoding lactate dehydrogenase A, pyruvate dehydrogenase kinase 1, BNIP3, cytochrome c oxidase subunit 4-2, mitochondrial protease LON, and microRNA miR-210. ► HIF-1 is a critical mediator of hypoxic and ischemic cardiac preconditioning. Further studies are required to determine whether regulation of myocardial metabolism plays a key role in preconditioning.

Keywords

Electron transport chain
Heart
Myocardial
Oxygen
Reactive oxygen species
Respiration

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This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.