title: Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.
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.
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.|Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lussey-Lepoutre
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Kate E R
authors.initials: KE
authors.lastname: Hollinshead
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Ludwig
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Menara
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Morin
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Luis-Jaime
authors.initials: LJ
authors.lastname: Castro-Vega
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.|Metabolic Biochemistry Laboratory, Hôpital Necker-Enfants Malades, F-75015 Paris, France.|INSERM, Unit 1124, F-75015 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Martinelli
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.|Metabolic Biochemistry Laboratory, Hôpital Necker-Enfants Malades, F-75015 Paris, France.|INSERM, Unit 1124, F-75015 Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Metallo
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.|Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
authors.forename: Judith
authors.identifier: http://orcid.org/0000-0001-8190-5853
authors.initials: J
authors.lastname: Favier
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Daniel A
authors.identifier: http://orcid.org/0000-0003-0499-2732
authors.initials: DA
authors.lastname: Tennant
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018358:Neuroendocrine Tumors / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010235:Paraganglioma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C491545:SDHD protein, human; D001224:Aspartic Acid; D019289:Pyruvic Acid; D042963:Electron Transport Complex II; C574938:SDHD protein, mouse; D013385:Succinate Dehydrogenase