title: Fumarate induces redox-dependent senescence by modifying glutathione metabolism.
abstract: Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Cardaci
authors.affiliation: The Blavatnik School of Computer Science-Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Livnat
authors.initials: L
authors.lastname: Jerby
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Elaine D
authors.initials: ED
authors.lastname: MacKenzie
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Sciacovelli
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: T Isaac
authors.initials: TI
authors.lastname: Johnson
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Gaude
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Ayala
authors.initials: A
authors.lastname: King
authors.affiliation: School of Veterinary Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Joshua D G
authors.initials: JD
authors.lastname: Leach
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 16 Richmond Street, Glasgow G1 1XQ, UK.
authors.forename: RuAngelie
authors.initials: R
authors.lastname: Edrada-Ebel
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Hedley
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Morrice
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: 1] The Blavatnik School of Computer Science-Tel Aviv University, Tel Aviv 69978, Israel [2] The Sackler School of Medicine-Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D002853:Chromatography, Liquid; D019295:Computational Biology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005649:Fumarate Hydratase / Q000737:chemistry; D005650:Fumarates / Q000737:chemistry*; D005973:Glutamine / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D059467:Transcriptome
chemical_list: D005650:Fumarates; D005973:Glutamine; D005649:Fumarate Hydratase; D005978:Glutathione