Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Citations Over TimeTop 10% of 2015 papers

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.

Related Papers

• → Global Transcription Analysis of Krebs Tricarboxylic Acid Cycle Mutants Reveals an Alternating Pattern of Gene Expression and Effects on Hypoxic and Oxidative Genes(2003)133 cited
• → Quantification of Fumarate and Investigation of Endogenous and Exogenous Fumarate Stability in Rat Plasma by LC–MS/MS(2016)8 cited
• → Mitochondrial activity during citric acid production by Aspergillus niger(1972)35 cited
• → The visualization by affinity electrophoresis of a specific association between the consecutive citric acid cycle enzymes fumarase and malate dehydrogenase(1989)28 cited
• → Tricarboxylic acid cycle enzymes of a pseudophyllid cestode Penetrocephalus ganapatii(1990)1 cited