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Nat Commun. 2015 Jan 23;6:6001. doi: 10.1038/ncomms7001.

Fumarate induces redox-dependent senescence by modifying glutathione metabolism.

Author information

1
Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
2
The Blavatnik School of Computer Science-Tel Aviv University, Tel Aviv 69978, Israel.
3
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
4
Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
5
School of Veterinary Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK.
6
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 16 Richmond Street, Glasgow G1 1XQ, UK.
7
1] The Blavatnik School of Computer Science-Tel Aviv University, Tel Aviv 69978, Israel [2] The Sackler School of Medicine-Tel Aviv University, Tel Aviv 69978, Israel.

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.

PMID:
25613188
PMCID:
PMC4340546
DOI:
10.1038/ncomms7001
[Indexed for MEDLINE]
Free PMC Article
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