Fumarate induces redox-dependent senescence by modifying glutathione metabolism.

TitleFumarate induces redox-dependent senescence by modifying glutathione metabolism.
Publication TypeJournal Article
AuthorsZheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, T Johnson I, Gaude E, King A, Leach JDG, Edrada-Ebel RA, Hedley A, Morrice NA, Kalna G, Blyth K, Ruppin E, Frezza C, Gottlieb E
2015
JournalNat Commun
Volume6
Pages6001

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.

10.1038/ncomms7001
PubMed ID25613188
PubMed Central IDPMC4340546
Grant ListA18278 / / Cancer Research UK / United Kingdom
/ / Cancer Research UK / United Kingdom