Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Zheng, L. et al. (2015) Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nature Communications, 6, 6001. (doi: 10.1038/ncomms7001) (PMID:25613188) (PMCID:PMC4340546)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Leach, Dr Joshua and Zheng, Mr Liang and Blyth, Professor Karen and Kalna, Dr Gabriela and Gottlieb, Professor Eyal and MacKenzie, Mrs Elaine and Cardaci, Dr Simone and King, Dr Ayala and Frezza, Mr Christian and Morrice, Dr Nicholas
Authors: 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., and Gottlieb, E.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2015 Macmillan Publishers Limited
First Published:First published in Nature Communications 6:6001
Publisher Policy:Reproduced under a Creative Commons License

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