Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning.
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.
Semenza
Gregg L
GL
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. gsemenza@jhmi.edu
D015720:5'-Nucleotidase / Q000096:biosynthesis; D000818:Animals; D015687:Cell Hypoxia; D003576:Electron Transport Complex IV / Q000378:metabolism; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species / Q000378:metabolism
C508686:BNip3 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D007506:Iron-Sulfur Proteins; C549325:MIRN210 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D003576:Electron Transport Complex IV; D017346:Protein Serine-Threonine Kinases; D015720:5'-Nucleotidase; D010100:Oxygen