HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Open accessAbstract
The HIF-1 transcription factor drives hypoxic gene expression changes that are thought to be adaptive for cells exposed to a reduced-oxygen environment. For example, HIF-1 induces the expression of glycolytic genes. It is presumed that increased glycolysis is necessary to produce energy when low oxygen will not support oxidative phosphorylation at the mitochondria. However, we find that while HIF-1 stimulates glycolysis, it also actively represses mitochondrial function and oxygen consumption by inducing pyruvate dehydrogenase kinase 1 (PDK1). PDK1 phosphorylates and inhibits pyruvate dehydrogenase from using pyruvate to fuel the mitochondrial TCA cycle. This causes a drop in mitochondrial oxygen consumption and results in a relative increase in intracellular oxygen tension. We show by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.
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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 Papandreou et al., 2006
During hypoxia, mitochondrial respiration is repressed, causing cells to adaptively sink electrons onto pyruvate through lactate dehydrogenase, generating lactate in the cytosol.
“During hypoxia, mitochondrial respiration is repressed, causing cells to adaptively sink electrons onto pyruvate through lactate dehydrogenase (LDH), generating lactate in the cytosol.17”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [17]
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 Papandreou et al., 2006
PDK1 represses mitochondrial function by antagonizing PDH, a rate-limiting enzyme for pyruvate conversion to acetyl-coenzyme A and entry into the tricarboxylic acid cycle.
“PDK1 represses mitochondrial function by antagonizing the function of pyruvate dehydrogenase (PDH), a rate-limiting enzyme for pyruvate conversion to acetyl–coenzyme A and entry into the tricarboxylic acid cycle (112).”
From Hypoxic control of metastasis (2016) · cites this paper as [112]
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 Papandreou et al., 2006
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- Authors
- Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Denko, Nicholas C.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 3
- Issue
- 3
- Pages
- 187-197
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2027705428
- Semantic Scholar
- fc762a0d5a2b764dd3de22ba3cd1e1bff06659c9
- Cited by
- 2,267
- References
- 47
- Citations by year
- 2026: 98 · 2025: 98 · 2024: 125 · 2023: 113 · 2022: 132 · 2021: 166 · 2020: 144 · 2019: 115 · 2018: 102 · 2017: 118 · 2016: 129 · 2015: 127 · 2014: 126 · 2013: 113 · 2012: 110
- FWCI
- 33.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA067166, CA 67166)
- 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 › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- HIF-1, hypoxia adaptation, mitochondrial oxygen consumption, pyruvate dehydrogenase kinase 1, pyruvate dehydrogenase, glycolysis, TCA cycle, intracellular oxygen tension, cell death, tirapazamine, transcriptional regulation
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Adaptation, Physiological, Animals, Cells, Cultured, Humans, Mitochondria, Oxygen Consumption, Protein Kinases, Down-Regulation, Cell Hypoxia, Up-Regulation, Apoptosis, Protein Serine-Threonine Kinases, Mice, Knockout, Computational Biology, Genomics, Mitochondrial Proteins, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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