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)

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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:Gottlieb, Professor Eyal and Van Den Broek, Mr Niels and Tumanov, Mr Sergey and MacKenzie, Mrs Elaine and Strathdee, Dr Douglas and Blyth, Dr Karen 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
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 > Institute 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.

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