Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism

Charlotte Lussey-Lepoutre, Kate E. R. Hollinshead, Christian Ludwig, Mélanie Menara, Aurélie Morin, Luis-Jaime Castro-Vega, Seth J. Parker, Maxime Janin, Cosimo Martinelli, Chris Ottolenghi, Christian Metallo, Anne-Paule Gimenez-Roqueplo, Judith Favier () and Daniel A. Tennant ()
Additional contact information
Charlotte Lussey-Lepoutre: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Kate E. R. Hollinshead: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham
Christian Ludwig: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham
Mélanie Menara: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Aurélie Morin: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Luis-Jaime Castro-Vega: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Seth J. Parker: University of California, San Diego
Maxime Janin: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine
Cosimo Martinelli: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Chris Ottolenghi: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine
Christian Metallo: University of California, San Diego
Anne-Paule Gimenez-Roqueplo: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Judith Favier: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP
Daniel A. Tennant: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.

Date: 2015
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DOI: 10.1038/ncomms9784

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