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

Jung Whan Kim, Irina Tchernyshyov, Gregg L. Semenza, Chi V. Dang

Research output: Contribution to journalArticlepeer-review

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-1α 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.

Original languageEnglish (US)
Pages (from-to)177-185
Number of pages9
JournalCell Metabolism
Volume3
Issue number3
DOIs
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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