¹Graduate Program of Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
²Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
³Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
⁴Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
⁵Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
⁶Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
⁷Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
⁸Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
⁹McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Received 13 December 2005;  revised 19 January 2006;  accepted 8 February 2006.  Published: March 7, 2006.  Available online 7 March 2006.

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.

Author Keywords: SIGNALING