Fumarate induces redox-dependent senescence by modifying glutathione metabolism

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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. 6001. ISSN 2041-1723 (https://doi.org/10.1038/ncomms7001)

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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.

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