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

Cardaci, S. et al. (2015) Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nature Cell Biology, 17, pp. 1317-1326. (doi: 10.1038/ncb3233) (PMID:26302408) (PMCID:PMC4591470)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blyth, Professor Karen and Gottlieb, Professor Eyal and Van Den Broek, Mr Niels and Vazquez, Alexei and Tumanov, Dr Sergey and MacKenzie, Mrs Elaine and Mackay, Dr Gillian and Kamphorst, Dr Jurre and Bulusu, Dr Vinay and Nixon, Mr Colin and Zheng, Mr Liang and Kalna, Dr Gabriela and Stevenson, Dr David and Cardaci, Dr Simone and Strathdee, Mr Douglas
• 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., and Gottlieb, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Cell Biology
• Publisher: Nature Publishing Group
• ISSN: 1465-7392
• ISSN (Online): 1476-4679
• Copyright Holders: Copyright © 2015 Nature Publishing Group
• First Published: First published in Nature Cell Biology 17:1317-1326
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.