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

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, Stewart Fleming, Francesca Schiavi, Gabriela Kalna, Karen Blyth, Douglas Strathdee, Eyal Gottlieb

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1317-1326
Number of pages10
JournalNature Cell Biology
Volume17
Issue number10
DOIs
Publication statusPublished - Oct 3 2015

ASJC Scopus subject areas

  • Cell Biology

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