We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis.
- Authors
Tumanov, Sergey; Bulusu, Vinay; Kamphorst, Jurre J.; Cardaci, Simone; Zheng, Liang; MacKay, Gillian; van den Broek, Niels J. F.; MacKenzie, Elaine D.; Nixon, Colin; Stevenson, David; Vazquez, Alexei; Kalna, Gabriela; Blyth, Karen; Strathdee, Douglas; Gottlieb, Eyal; Fleming, Stewart; Schiavi, Francesca
- 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.
- Subjects
CANCER cell proliferation; CANCER cell growth; ENZYME deficiency; SUCCINATE dehydrogenase; CELL metabolism; EXTRACELLULAR enzymes; PYRUVATE carboxylase; KREBS cycle
- Publication
Nature Cell Biology, 2015, Vol 17, Issue 10, p1317
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb3233