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Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
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Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
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Journal Article
Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
2015
Overview
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.
SDH inactivation is associated with cancer susceptibility. Cardaci
et al.
report a metabolic vulnerability in SDH-deficient cells, by showing that they depend on pyruvate carboxylation for the production of aspartate, proliferation and tumour growth.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/89
/ 38/1
/ 38/77
/ 42/41
/ 45/23
/ 631/67
/ 64/60
/ 82/16
/ 82/29
/ 82/58
/ Animals
/ Aspartic Acid - biosynthesis
/ Carboxylic Acids - metabolism
/ Carcinoma, Renal Cell - genetics
/ Carcinoma, Renal Cell - metabolism
/ Cell Transformation, Neoplastic - genetics
/ Cell Transformation, Neoplastic - metabolism
/ Enzymes
/ Humans
/ Kidney Neoplasms - metabolism
/ Male
/ Pyruvate Carboxylase - metabolism
