The Proto-oncometabolite Fumarate Binds Glutathione to Amplify ROS-dependent signaling

Lucas B. Sullivan, Eva Martinez-Garcia, Hien Nguyen, Andrew R. Mullen, Eric Dufour, Sunil Sudarshan, Jonathan D. Licht, Ralph J. Deberardinis, Navdeep S. Chandel

Research output: Contribution to journalArticlepeer-review

193 Scopus citations


The 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 invitro and invivo 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.

Original languageEnglish
Pages (from-to)236-248
Number of pages13
JournalMolecular Cell
Issue number2
StatePublished - 25 Jul 2013
Externally publishedYes


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