title: Dual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumors.
abstract: Mutations in succinate dehydrogenase (SDH) are associated with tumor development and neurodegenerative diseases. Only in tumors, loss of SDH activity is accompanied with the loss of complex I activity. Yet, it remains unknown whether the metabolic phenotype of SDH mutant tumors is driven by loss of complex I function, and whether this contributes to the peculiarity of tumor development versus neurodegeneration. We addressed this question by decoupling loss of SDH and complex I activity in cancer cells and neurons. We found that sole loss of SDH activity was not sufficient to recapitulate the metabolic phenotype of SDH mutant tumors, because it failed to decrease mitochondrial respiration and to activate reductive glutamine metabolism. These metabolic phenotypes were only induced upon the additional loss of complex I activity. Thus, we show that complex I function defines the metabolic differences between SDH mutation associated tumors and neurodegenerative diseases, which could open novel therapeutic options against both diseases.
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB Leuven, 3000 Leuven, Belgium; Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Doriane
authors.initials: D
authors.lastname: Lorendeau
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB Leuven, 3000 Leuven, Belgium; Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Rinaldi
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Ruben
authors.initials: R
authors.lastname: Boon
authors.affiliation: Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Spincemaille
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB Leuven, 3000 Leuven, Belgium; Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Kristine
authors.initials: K
authors.lastname: Metzger
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6, Avenue du Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Christian
authors.initials: C
authors.lastname: Jäger
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB Leuven, 3000 Leuven, Belgium; Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Christen
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6, Avenue du Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: VIB Center for the Brain and Disease Research, VIB Leuven, 3000 Leuven, Belgium; Department of Human Genetics and Leuven Research Institute for Neurodegenerative Diseases, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuenen
authors.affiliation: Laboratory for Systems Biology, VIB Center for Microbiology, VIB Leuven, 3000 Leuven, Belgium; CMPG Laboratory for Genetics and Genomics, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Voordeckers
authors.affiliation: VIB Center for the Brain and Disease Research, VIB Leuven, 3000 Leuven, Belgium; Department of Human Genetics and Leuven Research Institute for Neurodegenerative Diseases, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium; Cardiology Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vermeersch
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Verfaillie
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6, Avenue du Swing, L-4367 Belvaux, Luxembourg.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB Leuven, 3000 Leuven, Belgium; Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, 3000 Leuven, Belgium. Electronic address: sarah-maria.fendt@vib-kuleuven.be.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
mesh_terms: D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D013385:Succinate Dehydrogenase; D042967:Electron Transport Complex I
keywords: (13)C metabolic flux analysis; 3-nitropropionic acid (PubChem CID: 1678); Ataxia; Atpenin A5 (PubChem CID: 54676868); CB-839 (PubChem CID: 71577426); Complex I of the electron transport chain; Gastrointestinal stromal tumors; Leigh syndrome; Leukodystrophy; Mitochondrial respiration; Paraganglioma; Pyruvate carboxylase; Reductive glutamine metabolism; SDH mutations; Succinate dehydrogenase; rotenone (PubChem CID: 6758)