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

We found that hypoxia-inducible factor 1 actively suppresses metabolism through the tricarboxylic acid cycle by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1

Jung-whan Kim; Irina Tchernyshyov; Gregg L. Semenza; Chi V. Dang


Scholarcy highlights

  • The Pasteur effect, which describes the increased conversion of glucose to lactate in hypoxic cells, has been considered a critical cellular metabolic adaptation to hypoxia for over a century
  • Similar results were obtained by immunoblot assay of hexokinase 2, which is the product of a known hypoxia-inducible factor 1 target gene
  • We hypothesized that active suppression of the tricarboxylic acid cycle and shunting of pyruvate to lactate via inactivation of pyruvate dehydrogenase by pyruvate dehydrogenase kinase 1 is required for cell survival under prolonged hypoxic conditions
  • Pasteur described over a century ago that hypoxic cells increase the conversion of glucose to lactate, an effect that to date had been primarily attributed to the activation of glycolysis by hypoxia-inducible transcription factors HIF1a and/or HIF2a
  • We propose that the induction of PDK1 is necessary to prevent excessive mitochondrial reactive oxygen species production and to shunt pyruvate toward lactate and regenerate NAD+, which permits continued glycolysis and ATP production under hypoxia
  • B) PDK1 induction in P493-6 cells exposed to 100 mM CoCl2 under normoxic conditions
  • Along with the findings by Papandreou et al that PDK1 decreases mitochondrial oxygen consumption and function, our observations suggest that enforced PDK1 expression rescued Hif1a2/2 mouse embryo fibroblasts by inactivating PDH, decreasing mitochondrial oxygen consumption and function, thereby reducing hypoxic mitochondrial ATP consumption for maintenance of mitochondrial membrane potential
  • 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 reactive oxygen species production

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