The Proto-oncometabolite Fumarate Binds Glutathione to Amplify ROS-Dependent Signaling

•FH loss increases fumarate resulting in mitochondrial ROS activation of HIF-1•Fumarate covalently bonds glutathione to produce succinated glutathione (GSF)•GSF is a substrate of glutathione reductase and consumes NADPH to enhance ROS•Increased ROS due to FH deficiency contributes to hypermethylation of histones

SummaryThe tricarboxylic acid cycle enzyme fumarate hydratase (FH) has been identified as a tumor suppressor in a subset of human renal cell carcinomas. Human FH-deficient cancer cells display high fumarate concentration and ROS levels along with activation of HIF-1. The underlying mechanisms by which FH loss increases ROS and HIF-1 are not fully understood. Here, we report that glutamine-dependent oxidative citric acid cycle metabolism is required to generate fumarate and increase ROS and HIF-1 levels. Accumulated fumarate directly bonds the antioxidant glutathione in vitro and in vivo to produce the metabolite succinated glutathione (GSF). GSF acts as an alternative substrate to glutathione reductase to decrease NADPH levels and enhance mitochondrial ROS and HIF-1 activation. Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS.

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