Pyruvate Carboxylation Enables Growth of SDH-deficient Cells by Supporting Aspartate Biosynthesis

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2015 Aug 25

PMID 26302408

Citations 151

Authors

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

Affiliations

Soon will be listed here.

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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