Journal
NATURE CELL BIOLOGY
Volume 17, Issue 10, Pages 1317-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3233
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Funding
- Cancer Research UK
- FEBS long-term fellowship
- Cancer Research UK [22311, 17728, 18278] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [21140] Funding Source: researchfish
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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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