Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism
Open accessAbstract
The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.
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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 Lussey-Lepoutre et al., 2015
FH and SDH mutations create truncal metabolic aberrations, induce permanent restructuring of the TCA cycle, and result in numerous metabolic liabilities in preclinical models.
“FH and SDH mutations also create truncal metabolic aberrations. These mutations induce permanent restructuring of the TCA cycle and result in numerous metabolic liabilities in preclinical models (106–108).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [107]
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 [92]
Under conditions of hypoxia or impaired mitochondrial respiration, certain reactions of the TCA cycle reverse to support glutamine-dependent reductive carboxylation.
“For example, under conditions of hypoxia or impaired mitochondrial respiration, certain reactions of the TCA cycle reverse to support glutamine-dependent reductive carboxylation (92, 122, 123).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [92]
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References 41 · Cited by 227
- Authors
- Lussey-Lepoutre, C., Hollinshead, K. E. R., Ludwig, C., Menara, M., Morin, A., Castro-Vega, L.-J., Parker, S. J., Janin, M., Martinelli, C., Ottolenghi, C., Metallo, C., Gimenez-Roqueplo, A.-P., Favier, J., & Tennant, D. A.
- Affiliations
- University of Birmingham (GB)
- Inserm (FR)
- University of California San Diego (US)
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Favier, Judith
- Tennant, Daniel A.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-11-02
- Volume
- 6
- Issue
- 1
- Pages
- 8784-8784
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4632646
- OpenAlex
- W2337267398
- Cited by
- 227
- References
- 41
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 20 · 2023: 23 · 2022: 24 · 2021: 17 · 2020: 33 · 2019: 27 · 2018: 14 · 2017: 23 · 2016: 17
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Funders
- AstraZeneca
- European Commission (2007–2013, FP7 2007-2013, 259735, FP7/2007)
- University of Birmingham
- Agence Nationale de la Recherche (ANR-2011-JCJC-00701)
- National Institutes of Health (FP7/2007-2013)
- Biotechnology and Biological Sciences Research Council
- National Cancer Institute (R01CA188652)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- succinate dehydrogenase, pyruvate carboxylase, TCA cycle, aspartate metabolism, non-essential amino acids, metabolic plasticity, paraganglioma, cancer metabolism, cell proliferation, metabolic vulnerability
- MeSH terms
- Animals, Aspartic Acid, Humans, Membrane Proteins, Oxidative Phosphorylation, Paraganglioma, Succinate Dehydrogenase, Mice, Knockout, Neuroendocrine Tumors, Pyruvic Acid, Electron Transport Complex II, Mice
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