Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
Open accessAbstract
Succinate dehydrogenase (SDH) is a heterotetrameric nuclear-encoded complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid cycle. Loss-of-function mutations in any of the SDH genes are associated with cancer formation. However, the impact of SDH loss on cell metabolism and the mechanisms enabling growth of SDH-defective cells are largely unknown. Here, we generated Sdhb-ablated kidney mouse cells and used comparative metabolomics and stable-isotope-labelling approaches to identify nutritional requirements and metabolic adaptations to SDH loss. We found that lack of SDH activity commits cells to consume extracellular pyruvate, which sustains Warburg-like bioenergetic features. We further demonstrated that pyruvate carboxylation diverts glucose-derived carbons into aspartate biosynthesis, thus sustaining cell growth. By identifying pyruvate carboxylase as essential for the proliferation and tumorigenic capacity of SDH-deficient cells, this study revealed a metabolic vulnerability for potential future treatment of SDH-associated malignancies.
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SDH-defective cells upregulate pyruvate carboxylase protein expression in culture and in tumors to synthesize aspartate from glucose.
“To cope with TCA cycle truncation and still produce aspartate, SDH defective cells upregulate PC protein expression in culture and in tumors to synthesize aspartate from glucose (Cardaci et al., 2015; Lussey-Lepoutre et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Cardaci et al., 2015
PC is essential for growth of SDH-mutant cells, which exhibit a truncated TCA cycle and require an alternative source of OAA.
“PC is essential for growth of succinate dehydrogenase (SDH)–mutant cells, which exhibit a truncated TCA cycle and thus require an alternative source of OAA to support TCA cycle function and sustain aspartate production for anabolic pathways (91, 92).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [91]
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- [18]Xiao M Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumour suppressors Genes Dev 2012 26 1326 1338 22677546 PMC3387660
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“PC is essential for growth of succinate dehydrogenase (SDH)– mutant cells, which exhibit a truncated TCA cycle and thus require an alternative source of OAA to support TCA cycle function and sustain aspartate production for anabolic pathways (91, 92).”
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- Authors
- Cardaci, S., Zheng, L., MacKay, G., van den Broek, N. J. F., MacKenzie, E. D., Nixon, C., Stevenson, D., Tumanov, S., Bulusu, V., Kamphorst, J. J., Vazquez, A., Fleming, S., Schiavi, F., Kalna, G., Blyth, K., Strathdee, D., & Gottlieb, E.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Dundee (GB)
- Istituto Oncologico Veneto (IT)
- Corresponding author
- Gottlieb, Eyal
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-08-24
- Volume
- 17
- Issue
- 10
- Pages
- 1317-1326
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4591470
- OpenAlex
- W1483430612
- Cited by
- 286
- References
- 44
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 22 · 2023: 34 · 2022: 29 · 2021: 24 · 2020: 22 · 2019: 29 · 2018: 24 · 2017: 25 · 2016: 31 · 2015: 6
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Cancer Research UK (A18278, 18278, 17728, 22311, 21140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- succinate dehydrogenase, pyruvate carboxylation, pyruvate carboxylase, aspartate biosynthesis, Warburg effect, metabolic vulnerability, carcinogenesis, TCA cycle, cancer metabolism, metabolic reprogramming
- MeSH terms
- Animals, Aspartic Acid, Carboxylic Acids, Carcinoma, Renal Cell, Cell Line, Transformed, Cell Transformation, Neoplastic, Cells, Cultured, Humans, Kidney, Kidney Neoplasms, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Pyruvate Carboxylase, Succinate Dehydrogenase, Immunoblotting, Mice, Knockout, Pyruvic Acid, RNA Interference, Cell Proliferation, Metabolomics, Mice, 129 Strain
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