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Loss of Succinate Dehydrogenase Activity Results in Dependency on Pyruvate Carboxylation for Cellular Anabolism

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Loss of Succinate Dehydrogenase Activity Results in Dependency on Pyruvate Carboxylation for Cellular Anabolism ARTICLE Received 28 Jul 2015 | Accepted 2 Oct 2015 | Published 2 Nov 2015 DOI: 10.1038/ncomms9784 OPEN Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism Charlotte Lussey-Lepoutre1,2,3,*, Kate E.R. Hollinshead4,*, Christian Ludwig4,*, Me´lanie Menara1,2,*, Aure´lie Morin1,2, Luis-Jaime Castro-Vega1,2, Seth J. Parker5, Maxime Janin2,6,7, Cosimo Martinelli1,2, Chris Ottolenghi2,6,7, Christian Metallo5, Anne-Paule Gimenez-Roqueplo1,2,3, Judith Favier1,2,** & Daniel A. Tennant4,** 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. 1 INSERM, UMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, France. 2 Universite´ Paris Descartes, Sorbonne Paris Cite´, Faculte´ de Me´decine, F-75006 Paris, France. 3 Department of Genetics, Assistance Publique-Hoˆpitaux de Paris, Hoˆpital Europe´en Georges Pompidou, Paris, France. 4 Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. 5 Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA. 6 Metabolic Biochemistry Laboratory, Hoˆpital Necker-Enfants Malades, F-75015 Paris, France. 7 INSERM, Unit 1124, F-75015 Paris, France. * These authors contributed equally to this work. ** These authors jointly supervised the work. Correspondence and requests for materials should be addressed to J.F. (email: [email protected]) or to D.A.T. (email: [email protected]). NATURE COMMUNICATIONS | 6:8784 | DOI: 10.1038/ncomms9784 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms9784 heochromocytoma (PCC) and paraganglioma (PGL) are metabolism, with specific reference to the non-essential amino neuroendocrine tumours arising in the adrenal medulla and acids alanine, aspartate and glutamate as the most affected Pin paraganglia of the autonomous nervous system, (Supplementary Table 1c,d). We performed an analysis of the respectively. Since the original discovery of SDHD mutations in steady-state concentrations of these amino acids using the hereditary PGL in 2000, the genes encoding all four proteins that previously characterized immortalized mouse chromaffin cell constitute the succinate dehydrogenase (SDH) complex as well as (imCC) lines (wild-type; WT, Sdhb À / À ; clones 6 and 8) as a the required assembly factor (SDH assembly factor 2: SDHAF2) model, which represent the cell type from which PCC arise in have been shown as tumour-suppressor genes in familial and patients. We found that all three amino acids identified from the apparently sporadic PCC and PGL1–5. Interestingly, SDHB transcriptomic screen were significantly altered in SDH-deficient mutation carriers were specifically shown to be predisposed to cells, with aspartate concentrations particularly affected (Fig. 1a). malignant6 and particularly aggressive forms of the disease7. In addition, steady-state concentrations of glycine, proline and The effects of all these mutations are to abolish SDH activity, serine were also altered, although the effect was not consistent which results in high steady-state intracellular concentrations of between the clones with respect to glycine and proline succinate3,4,8–11. (Supplementary Fig. 2a). To confirm the physiological A growing number of tricarboxylic acid (TCA) cycle significance of alterations in the concentrations of alanine, intermediates, namely succinate and fumarate, are now aspartate and glutamate, we performed a targeted analysis of considered oncometabolites, acting in part through the aberrant amino-acid concentrations in SDH-mutated human PCC/PGL activation of transcription factors and global epigenetic repro- tumours compared with non-SDH mutated ones. Alongside gramming11–13. Indeed, both SDH and fumarate hydratase- succinate, which was greatly elevated as expected in SDH-mutated mutant tumours have been shown to elicit a pseudohypoxic tumours, aspartate and the related amino acid, asparagine, phenotype through high steady-state levels of succinate and were both decreased (Fig. 1b). In addition, the change in serine fumarate, respectively11,14–16. Tumours arising from such concentration was also recapitulated (Supplementary Fig. 2b). mutations demonstrate stabilization and activation of the hypoxia-inducible transcription factors, HIF1 and 2, which have been shown to elicit hypoxia-like alterations in metabolism, such Sdhb À / À cells exhibit altered pyruvate metabolism. Aspartate as increased lactate dehydrogenase A (LDHA) expression and production in most cells occurs mainly through oxidative TCA lactate production8,9,17,18. However, the direct metabolic cycle metabolism, which SDH-deficient cells would be expected to consequences of SDH loss are as yet uncharacterized. It was lack. We therefore investigated the steady-state concentrations recently shown that loss of another TCA cycle enzyme associated of TCA cycle intermediates, and observed, in addition to the with a hereditary cancer syndrome, fumarate hydratase, led to previously reported truncated TCA cycle (high succinate, low significant metabolic reprogramming of the mitochondria, which fumarate and malate11,16), a significantly reduced steady-state was essential for continued cell viability18,19. Indeed, both genetic citrate (Fig. 1c). Both reduced aspartate and citrate steady-state and hypoxia-mediated disruption of the TCA cycle has been concentrations suggest alterations in the metabolism of the suggested to result in alterations in cellular metabolic activity, glycolytic metabolite, pyruvate, which also represents the resulting in cells that are more reliant on reductive carboxylation glycolytic entry point into the TCA cycle. We investigated this of glutamine for the provision of carbon for anabolic purposes phenomenon by incubating both the imCC cell model, and a than oxidative TCA cycle metabolism20–22. These data suggested novel Sdhb À / À mouse adrenal fibroblast (MAF) cell line model that certain cell types are capable of re-wiring their metabolic (Supplementary Fig. 2c–e) with 13C-enriched glucose. Consistent network in response to the loss of a fully functional TCA cycle, with the pseudohypoxic phenotype previously reported in but that despite this, the resulting metabolic phenotype is capable SDH-deficient cells9,14, we noted increased lactate production of sustaining oncogenic transformation. and excretion (Fig. 1d), along with the additional observation We therefore sought to investigate how cells deficient in SDH of increased alanine synthesis and excretion (Supplementary activity through deletion of the SDHB subunit maintain their Fig. 3a). proliferation and viability. We found that in the absence of a fully Significant synthesis of metabolites arising downstream from functional TCA cycle, cells become deficient for a number of pyruvate through the TCA cycle in both WT and Sdhb knockout key central carbon metabolites, such as citrate, malate and (KO) cells were also observed through the detection of label aspartate. Aspartate synthesis is maintained through pyruvate incorporation from glucose into glutamate, succinate and carboxylation, which SDH-deficient cells become critically aspartate (Fig. 2a–c). The isotopomers of glutamate and aspartate dependent on for their proliferation and survival. Finally, produced in the Sdhb WT and KO, however, were significantly we found that, despite the use of reductive carboxylation to different suggesting the implication of differential metabolic metabolize glutamine, SDH-deficient cells are unable to reverse pathways (Fig. 2a,c, and Supplementary Fig. 3b). Mitochondrial their deficiency. pyruvate can either be oxidatively decarboxylated by pyruvate dehydrogenase (PDH) to form acetyl coA, or carboxylated by PC to form oxaloacetate (OAA). In WT cells, the 13C-[4,5]-glutamate Results species was the major isotopomer observed from 13C-[1,2]- Amino-acid metabolism is perturbed in SDH-mutated tumours. glucose, consistent with the oxidative decarboxylation of pyruvate To explore predicted changes in tumourigenic metabolic path- by PDH (Fig. 2a,d, and Supplementary Fig. 3b). However, in Sdhb ways, we performed a bioinformatic analysis of the transcriptome KO cells, the relative contribution of the 13C-[4,5]-glutamate was of 186 PCC/PGL (including 23 SDH-mutated tumours) using a reduced by about 50%, and replaced by 13C-[2,3]-glutamate, previously described subset of metabolic genes identified as being which represents incorporation of labelled
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