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

LucasB Sullivan, Eva Martinez-Garcia, Hien Nguyen, AndrewR Mullen, Eric Dufour, Sunil Sudarshan, JonathanD Licht, RalphJ Deberardinis, NavdeepS Chandel

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

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 (US)
Pages (from-to)236-248
Number of pages13
JournalMolecular cell
Volume51
Issue number2
DOIs
StatePublished - Jul 25 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Sullivan, L., Martinez-Garcia, E., Nguyen, H., Mullen, A., Dufour, E., Sudarshan, S., Licht, J., Deberardinis, R., & Chandel, N. (2013). The Proto-oncometabolite Fumarate Binds Glutathione to Amplify ROS-dependent signaling. Molecular cell, 51(2), 236-248. https://doi.org/10.1016/j.molcel.2013.05.003