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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • 5'-Nucleotidase / biosynthesis
  • Animals
  • Cell Hypoxia
  • Electron Transport Complex IV / metabolism
  • Glycolysis
  • Homeostasis
  • Humans
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Iron-Sulfur Proteins / metabolism
  • Ischemic Preconditioning, Myocardial*
  • Membrane Proteins / biosynthesis
  • Mice
  • MicroRNAs / biosynthesis
  • Mitochondria, Heart / metabolism*
  • Mitochondrial Proteins / biosynthesis
  • Myocardium / metabolism*
  • Oxygen / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Reactive Oxygen Species / metabolism

Substances

  • BNip3 protein, mouse
  • Hypoxia-Inducible Factor 1
  • Iron-Sulfur Proteins
  • MIRN210 microRNA, mouse
  • Membrane Proteins
  • MicroRNAs
  • Mitochondrial Proteins
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Reactive Oxygen Species
  • Electron Transport Complex IV
  • Protein-Serine-Threonine Kinases
  • 5'-Nucleotidase
  • Oxygen