Article | Published:

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

Nature Cell Biology volume 17, pages 13171326 (2015) | Download Citation

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.

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Acknowledgements

We would like to acknowledge S. Tardito and Z. T. Schug for comments and interpretation of the results, A. King for editorial work, U. Srirangalingam for help in human specimen collection and the Beatson Institute mouse facility staff for housing of mice and xenograft measurements.

Author information

Affiliations

  1. Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK

    • Simone Cardaci
    • , Liang Zheng
    • , Gillian MacKay
    • , Niels J. F. van den Broek
    • , Elaine D. MacKenzie
    • , Colin Nixon
    • , David Stevenson
    • , Sergey Tumanov
    • , Vinay Bulusu
    • , Jurre J. Kamphorst
    • , Alexei Vazquez
    • , Gabriela Kalna
    • , Karen Blyth
    • , Douglas Strathdee
    •  & Eyal Gottlieb
  2. Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK

    • Sergey Tumanov
    • , Vinay Bulusu
    •  & Jurre J. Kamphorst
  3. Department of Pathology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK

    • Stewart Fleming
  4. Veneto Institute of Oncology IRCCS, Familial cancer clinic and oncoendocrinology, Via Gattamelata 64, 35128 Padova, Italy

    • Francesca Schiavi

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Contributions

S.C. conceived the study, designed and carried out the experiments, interpreted the data and wrote the manuscript; L.Z. carried out the untargeted metabolomic analysis; G.M., N.J.F.v.d.B. S.T., V.B., J.J.K. and A.V. supervised the targeted LC-MS and GC-MS analyses; E.D.M. supervised the generation of kidney cells; D. Strathdee and D. Stevenson generated genetically modified Sdhbfl/fl mice; G.K. carried out the bioinformatics and statistical analyses; C.N. carried out immunohistochemistry of human SDHB-associated RCC; S.F. carried out histopathological analysis of SDHB-related RCC; F.S. collected and provided human paraganglioma and pheochromocytoma samples; K.B. supervised animal work; E.G. conceived and supervised the study, interpreted the data and revised the manuscript. All the authors discussed the results and commented on the manuscript. This work was funded by Cancer Research UK. S.C. is the recipient of a FEBS long-term fellowship.

Competing interests

E.G. is a shareholder and a consultant of MetaboMed Israel, Ltd.

Corresponding author

Correspondence to Eyal Gottlieb.

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DOI

https://doi.org/10.1038/ncb3233

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