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Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Zheng, Liang and Cardaci, Simone and Jerby, Livnat and Mackenzie, Elaine D. and Sciacovelli, Marco and Johnson, T. Isaac and Gaude, Edoardo and King, Ayala and Leach, Joshua D.G. and Edrada-Ebel, RuAngelie and Hedley, Ann and Morrice, Nicholas A. and Kalna, Galbriela and Blyth, Karen and Ruppin, Eytan and Frezza, Christian and Gottlieb, Eyal (2015) Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nature Communications, 6. ISSN 2041-1723

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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.