title: The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling.
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 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.
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Sullivan
authors.forename: Eva
authors.initials: E
authors.lastname: Martinez-Garcia
authors.forename: Hien
authors.initials: H
authors.lastname: Nguyen
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mullen
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
authors.forename: Sunil
authors.initials: S
authors.lastname: Sudarshan
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Deberardinis
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D002853:Chromatography, Liquid; D005649:Fumarate Hydratase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D009249:NADP / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
chemical_list: D005650:Fumarates; C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D009249:NADP; D056466:Histone Demethylases; D005980:Glutathione Reductase; D005649:Fumarate Hydratase; D005978:Glutathione