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

J Kim, I Tchernyshyov, GL Semenza, CV Dang - Cell metabolism, 2006 - cell.com
J Kim, I Tchernyshyov, GL Semenza, CV Dang
Cell metabolism, 2006cell.com
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 …
Summary
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.
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