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Nat Cell Biol. 2015 Oct;17(10):1317-26. doi: 10.1038/ncb3233. Epub 2015 Aug 24.

Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis.

Author information

1
Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
2
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
3
Department of Pathology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
4
Veneto Institute of Oncology IRCCS, Familial cancer clinic and oncoendocrinology, Via Gattamelata 64, 35128 Padova, Italy.

Abstract

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.

PMID:
26302408
PMCID:
PMC4591470
DOI:
10.1038/ncb3233
[Indexed for MEDLINE]
Free PMC Article

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