Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Liang Zheng, Simone Cardaci, Livnat Jerby, Elaine D. MacKenzie, Marco Sciacovelli, T. Isaac Johnson, Edoardo Gaude, Ayala King, Joshua D. G. Leach, RuAngelie Edrada-Ebel, Ann Hedley, Nicholas A. Morrice, Gabriela Kalna, Karen Blyth, Eytan Ruppin, Christian Frezza () and Eyal Gottlieb ()
Additional contact information
Liang Zheng: Cancer Research UK, Beatson Institute
Simone Cardaci: Cancer Research UK, Beatson Institute
Livnat Jerby: The Blavatnik School of Computer Science—Tel Aviv University
Elaine D. MacKenzie: Cancer Research UK, Beatson Institute
Marco Sciacovelli: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre
T. Isaac Johnson: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre
Edoardo Gaude: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre
Ayala King: Institute of Cancer Sciences, University of Glasgow
Joshua D. G. Leach: School of Veterinary Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow
RuAngelie Edrada-Ebel: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde
Ann Hedley: Cancer Research UK, Beatson Institute
Nicholas A. Morrice: Cancer Research UK, Beatson Institute
Gabriela Kalna: Cancer Research UK, Beatson Institute
Karen Blyth: Cancer Research UK, Beatson Institute
Eytan Ruppin: The Blavatnik School of Computer Science—Tel Aviv University
Christian Frezza: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre
Eyal Gottlieb: Cancer Research UK, Beatson Institute

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7001

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