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, Galbriela Kalna, Karen Blyth, Eytan Ruppin, Christian Frezza, Eyal Gottlieb

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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.
Original languageEnglish
Article number6001
Number of pages12
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 23 Jan 2015

Keywords

  • ​fumarate hydratase
  • tricarboxilic acid cycle
  • renal cancer
  • succinic acid
  • cell biology

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    Zheng, L., Cardaci, S., Jerby, L., Mackenzie, E. D., Sciacovelli, M., Johnson, T. I., Gaude, E., King, A., Leach, J. D. G., Edrada-Ebel, R., Hedley, A., Morrice, N. A., Kalna, G., Blyth, K., Ruppin, E., Frezza, C., & Gottlieb, E. (2015). Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nature Communications, 6, [6001]. https://doi.org/10.1038/ncomms7001