Redox alterations induced by TCA cycle defects. Redox alterations induced by mutations in SDH, FH, and IDH are shown. Loss of function of SDH increases ROS levels leading to DNA mutations and HIF-1α stabilization. IDH1 and IDH2 (not shown) mutations decrease GSH and NADPH levels. (R)-2-HG, produced by oncogenic mutations in IDH1 and IDH2, triggers ROS accumulation. Defects in FH stimulate nuclear translocation of Nrf2 and the transcription of antioxidant enzymes through the succination of Keap1. Enzymes and metabolites involved in tumor formation and redox alterations are in red. Blue arrows indicate TCA cycle reactions. Dotted arrows indicate pathways modulating cell redox state.