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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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| 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: | 2041-1723 |
| 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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