HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia
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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.
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HIF-1 actively participates in metabolic reprogramming from the TCA cycle to glycolysis by directly targeting the gene encoding PDK1.
“Furthermore, Kim et al. provided the first evidence that HIF-1 actively participates in metabolic 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).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Kim et al., 2006
This metabolic adaptation is critical because of reduced entry of pyruvate into the TCA cycle by activated PDK1 and increased lactate secretion in hypoxia.
“This metabolic adaptation is critical because of the reduced entry of pyruvate into the TCA cycle by activated PDK1 and the increased lactate secretion in hypoxia66.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [66]
HIF-1 upregulates PDH kinase, LDHA, and other glycolytic genes to increase glycolysis, decreases TCA cycle activity, and reduces electron flux through mitochondrial complexes I, III, and IV.
“HIF-1 coordinately upregulates PDH kinase, LDHA, and other glycolytic genes to increase glycolysis; decreases the activity of the TCA cycle; and reduces electron flux through mitochondrial complexes I, III, and IV (214, 386).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [214]
Low oxygen levels activate HIFs, which bind hypoxia-response elements in target genes including LDHA and PDK1, leading to suppression of PDHC activity and increased aerobic glycolysis.
“For example, low oxygen levels activate the hypoxia-inducible transcription factors (HIFs), which bind to hypoxia-response elements within a number of target genes including LDH-A (LDHA) and PDK1, leading to suppression of PDHC activity with a concomitant increase in aerobic glycolysis (141).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [141]
HIF1α stabilization by hypoxia or oncogenic contexts triggers coordinated transcriptional upregulation of LDH-A and PDK1.
“Finally, stabilization of HIF1α by hypoxia or in various oncogenic contexts also triggers coordinated transcriptional upregulation of LDH-A and PDK1 (Kim et al., 2006; Papandreou et al., 2006).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Kim et al., 2006
Mpc knockdown causes metabolic reprogramming distinct from hypoxia-associated PDH inhibition, with an increased proportion of mitochondrial AcCoA derived from mitochondrial ME and PDH activity rather than reductive carboxylation.
“These results demonstrate that Mpc knockdown causes metabolic reprogramming that is distinct from hypoxia-associated PDH inhibition (Kim et al., 2006; Papandreou et al., 2006), with an increased proportion of mitochondrial AcCoA derived from mitochondrial ME and PDH activity rather than reductive carboxylation.”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Kim et al., 2006
HIF-1 activation inhibits mitochondrial metabolism of glucose carbon, in part by promoting expression of PDK1 to inhibit PDH activity.
“However, HIF-1 activation has the additional effect of inhibiting mitochondrial metabolism of glucose carbon, in part by promoting the expression of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit PDH activity (Kim et al., 2006; Papandreou et al., 2006).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Kim et al., 2006
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- Authors
- Kim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Dang, Chi V.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 3
- Issue
- 3
- Pages
- 177-185
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2033958147
- Cited by
- 3,905
- References
- 25
- Citations by year
- 2026: 185 · 2025: 233 · 2024: 255 · 2023: 242 · 2022: 278 · 2021: 294 · 2020: 274 · 2019: 241 · 2018: 219 · 2017: 207 · 2016: 224 · 2015: 211 · 2014: 176 · 2013: 171 · 2012: 152
- FWCI
- 39.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hv28180-13-0-0)
- National Heart, Lung, and Blood Institute (N01 HV-28180)
- National Cancer Institute (CA 57341, R01CA057341, CA52497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- HIF-1, pyruvate dehydrogenase kinase 1, hypoxia, metabolic switch, glycolysis, TCA cycle, pyruvate dehydrogenase, acetyl-CoA, reactive oxygen species, apoptosis, ATP production, transcriptional regulation, glucose metabolism
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Adaptation, Physiological, Animals, Cell Survival, Fibroblasts, Humans, Models, Biological, Phosphorylation, Protein Kinases, Cell Hypoxia, Gene Expression, Gene Expression Regulation, Enzymologic, Apoptosis, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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