Hypoxic Regulation of Glutamine Metabolism through HIF1 and SIAH2 Supports Lipid Synthesis that Is Necessary for Tumor Growth
Open accessAbstract
Recent reports have identified a phenomenon by which hypoxia shifts glutamine metabolism from oxidation to reductive carboxylation. We now identify the mechanism by which HIF-1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex alpha-ketoglutarate dehydrogenase (αKGDH). HIF-1 activation promotes SIAH2 targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the αKGDH complex (OGDH2). Knockdown of SIAH2, or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in αKGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis. 336KA OGDH2 expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immune-deficient mice. Reversal of hypoxic mitochondrial function may provide a novel target for the development of next-generation anti-cancer agents targeting tumor metabolism.
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Under tonic hypoxia, HIF1α upregulates glutaminolysis in an attempt to restore mitochondrial redox potential.
“Under tonic hypoxia, HIF1α is also known to upregulate glutaminolysis (78) in an attempt to restore mitochondrial redox potential, which is also indicated in our sample by negative association between hypoxanthine and glutamine (ρ = −0.159, P = 0.041, q = 0.098).”
From Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity (2019) · cites this paper as [78]
The Results section (page unavailable) reports that HIF1α stabilization inhibits mitochondrial glutamine oxidation and that glutamine uptake is slightly reduced under hypoxia, rather than showing upregulated glutaminolysis. The Discussion (page unavailable) describes a shift toward using glutamine to make citrate and support proliferation, not an attempt to restore mitochondrial redox potential. (LLM, conf=0.83)
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Experimental — accuracy not yet measuredHIF-1α activation induces GLS, which promotes the conversion of glutamine to glutamate.
“Additionally, HIF-1α activation promotes the induction of GLS, which promotes the conversion of glutamine to the metabolic intermediate, glutamate [60].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [60]
The Introduction (page unavailable) says glutaminase participates in the conversion of glutamine toward α-ketoglutarate via glutamate. It does not say HIF-1α induces GLS. The Results section (page unavailable) instead identifies reduced α-ketoglutarate dehydrogenase activity as the effect of HIF stabilization. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCertain cancer cells may use carbon sources such as glutamine or acetate to compensate for reduction in acetyl-CoA synthesis from glucose.
“Alternatively, certain cancer cells may use carbon sources such as glutamine or acetate to compensate for the reduction in acetyl-CoA synthesis from glucose [94,95].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [94]
The Introduction says glutamine-derived citrate can generate acetyl-CoA, and the Discussion describes glutamine as an alternative fuel when hypoxia reduces glucose-derived citrate. The Results also show decreased glucose incorporation and increased glutamine incorporation into lipids under hypoxia. Our copy does not support the sentence’s additional example of acetate. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCitrate generated by reductive carboxylation of α-KG is crucial for lipid synthesis under low-oxygen conditions.
“Citrate, generated by reductive carboxylation of α-KG, is especially crucial for lipid synthesis under low-oxygen conditions24,25.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [25]
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References 30 · Cited by 344
Research works printed but not linked: 1
- Metallo CM Gameiro PA Bell EL Mattaini KR Yang JJ Hiller K Jewell CM Johnson ZR Irvine DJ Guarente L 2012b Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia Nature 481 380 U166 22101433 PMC3710581
- Authors
- Sun, R. C., & Denko, N. C.
- Affiliations
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Corresponding author
- Denko, Nicholas C.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 19
- Issue
- 2
- Pages
- 285-292
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3920584
- OpenAlex
- W2069526715
- Semantic Scholar
- 545a334db364499d69f319839b1c0c87ac59978a
- Cited by
- 344
- References
- 30
- Citations by year
- 2026: 21 · 2025: 17 · 2024: 30 · 2023: 39 · 2022: 34 · 2021: 33 · 2020: 33 · 2019: 26 · 2018: 24 · 2017: 27 · 2016: 26 · 2015: 23 · 2014: 11
- FWCI
- 9.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA067166, R01CA163581, P30CA016058)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- hypoxia, glutamine metabolism, HIF-1, SIAH2, alpha-ketoglutarate dehydrogenase, ubiquitination, proteolysis, reductive carboxylation, glutamine oxidation, lipogenesis, tumor growth, cancer metabolism, citrate, mitochondrial function, anticancer drug targets
- MeSH terms
- Seven in Absentia Proteins, Animals, Glutamine, Humans, Mice, Nude, Nuclear Proteins, Oxygen Consumption, Mass Spectrometry, Cell Hypoxia, Ubiquitin-Protein Ligases, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1
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