Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7001
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Funding
- Cancer Research UK
- FEBS Long-Term Fellowship
- Edmond J. Safra bioinformatics centre
- Israeli Center of Research Excellence programme (I-CORE, Gene Regulation in Complex Human Disease Center) [41/11]
- Adams fellowship
- Israeli Science Foundation (ISF)
- Israeli Cancer Research Fund (ICRF)
- I-CORE programme
- MRC [MC_UP_1101/3, MC_UU_12022/6] Funding Source: UKRI
- Cancer Research UK [22311, 18278] Funding Source: researchfish
- Medical Research Council [MC_UU_12022/6, MC_UP_1101/3] Funding Source: researchfish
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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.
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