HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia

Cell Metab. 2006 Mar;3(3):177-85. doi: 10.1016/j.cmet.2006.02.002.

Abstract

Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.

Publication types

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

MeSH terms

  • Adaptation, Physiological*
  • Animals
  • Apoptosis
  • Cell Hypoxia / physiology*
  • Cell Survival
  • Fibroblasts / cytology
  • Gene Expression
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Models, Biological
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Reactive Oxygen Species

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Reactive Oxygen Species
  • Protein Kinases
  • Protein-Serine-Threonine Kinases