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

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.

• Authors: Jung-whan Kim, Irina Tchernyshyov, Gregg L Semenza, Chi V Dang
• Journal: Cell metabolism (Cell Metab) Vol. 3 Issue 3 Pg. 177-85 (Mar 2006) ISSN: 1550-4131 [Print] United States
• PMID: 16517405 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

• 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, metabolism)
• Mice
• Models, Biological
• Phosphorylation
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Reactive Oxygen Species