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

By Jung-whan Kim, Irina Tchernyshyov, G. Semenza, C. V. Dang. Cell Metabolism, 2006

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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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5ed1895b80555a510b8357f80db8f4dec8ac4f4d

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Citations in the corpus

The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche (2010, background): “It regulates both glycolysis and mitochondrial respiration, inducing a metabolic shift toward anaerobic glycolysis (Hägg and Wennström, 2005; Kim et al., 2006b; Marı́n-Hernández et al., 2009; Maxwell et al., 2007; Papandreou et al., 2006; Wang et al., 1995; Zhang et al., 2007).”
The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α (2010, positive): “On the other hand, Hif1a directly inhibits mitochondrial respiration by upregulating expression of the pyruvate dehydrogenase kinase (PDK) gene (Kim et al., 2006; Papandreou et al., 2006).”
Tumor suppressors and cell metabolism: a recipe for cancer growth. (2009, background): “In addition, HIF1 promotes the shunting of pyruvate away from mitochondria by up-regulating pyruvate dehydrogenase kinase 1 (PDK1) (Kim et al. 2006; Papandreou et al. 2006), a negative regulator of pyruvate dehydrogenase (PDH), the rate-limiting enzyme for pyruvate to acetyl-CoA conversion.”
The interplay between MYC and HIF in cancer (2008, background): “Acetyl-CoA is a key substrate for the Krebs cycle and the ensuing oxidative phosphorylation, such that its depletion results in diminished hypoxic mitochondrial respiratio”
Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “Concurrently, HIF-1 blocks mitochondrial energy metabolism by inducing PDK-1, which inhibits the conversion of pyruvate to acetyl-CoA, and by inhibiting mitochondrial biogenesis via c-Myc repression (Kim et al., 2006a; Zhang et al., 2007a).”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “The role of PDC in cancer progression remains inconclusive (Kim et al., 2006; Papandreou et al., 2006; Hitosugi et al., 2011; Kaplon et al., 2013; Sutendra et al., 2014).”
13 reasons why the brain is susceptible to oxidative stress (2018, background): “terminate mitochondrial O2 generation could initiate redox regulated intrinsic apoptosis [120,121].”
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. (2016, background): “Furthermore, Kim et al. provided the first evidence that HIF-1 actively participates inmetabolic reprogramming from the TCA cycle to glycolysis by showing that HIF-1 directly targets the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) (Kim et al., 2006).”