Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects
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Mammalian cells generate citrate by decarboxylating pyruvate in the mitochondria to supply the tricarboxylic acid (TCA) cycle. In contrast, hypoxia and other impairments of mitochondrial function induce an alternative pathway that produces citrate by reductively carboxylating α-ketoglutarate (AKG) via NADPH-dependent isocitrate dehydrogenase (IDH). It is unknown how cells generate reducing equivalents necessary to supply reductive carboxylation in the setting of mitochondrial impairment. Here, we identified shared metabolic features in cells using reductive carboxylation. Paradoxically, reductive carboxylation was accompanied by concomitant AKG oxidation in the TCA cycle. Inhibiting AKG oxidation decreased reducing equivalent availability and suppressed reductive carboxylation. Interrupting transfer of reducing equivalents from NADH to NADPH by nicotinamide nucleotide transhydrogenase increased NADH abundance and decreased NADPH abundance while suppressing reductive carboxylation. The data demonstrate that reductive carboxylation requires bidirectional AKG metabolism along oxidative and reductive pathways, with the oxidative pathway producing reducing equivalents used to operate IDH in reverse.
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α-KG is exported from mitochondria through SLC25A11 to the cytosol and participates in fatty acid biosynthesis and NADH generation.
“In addition, α-KG is exported from mitochondria through SLC25A11 to the cytosol21 and then participates in fatty acid biosynthesis and NADH generation22 (Fig. 1).”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [22]
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- Authors
- Mullen, A. R., Hu, Z., Shi, X., Jiang, L., Boroughs, L. K., Kovacs, Z., Boriack, R., Rakheja, D., Sullivan, L. B., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J.
- Affiliations
- Children's Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Northwestern University (US)
- National Institutes of Health (US)
- Corresponding author
- DeBerardinis, Ralph J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 7
- Issue
- 5
- Pages
- 1679-1690
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4057960
- OpenAlex
- W2005703314
- Cited by
- 337
- References
- 38
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 25 · 2023: 22 · 2022: 32 · 2021: 37 · 2020: 39 · 2019: 31 · 2018: 28 · 2017: 30 · 2016: 28 · 2015: 27 · 2014: 4
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Texas Southwestern Medical Center
- National Cancer Institute (R01CA157996)
- National Institute of General Medical Sciences (T32GM083831)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- reductive carboxylation, alpha-ketoglutarate oxidation, isocitrate dehydrogenase, NADPH, NADH, nicotinamide nucleotide transhydrogenase, citric acid production, mitochondrial dysfunction, hypoxia, cancer metabolism, TCA cycle, reducing equivalents
- MeSH terms
- Animals, Cell Line, Citric Acid Cycle, Cricetulus, Fumarate Hydratase, Cricetinae, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Mitochondria, Mutation, NAD, Neoplasms, Oxidation-Reduction, Cell Line, Tumor, NADP Transhydrogenase, AB-Specific
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