Fig. 2: Defenders of ferroptosis.
(1) Cystine is transported into the cytosol via the cystine/glutamate reverse transporter and metabolized to cysteine. Cysteine and intracellular glutamate are metabolized by glutamate. Cysteine ligase (GCL) catalyses the formation of Y-glutamate cysteine. The latter is catalyzed by glutathione synthetase (GS) and glycine (Gly) to produce glutathione. Glutathione peroxidase 4, assisted by the cofactor glutathione, inhibits the accumulation of phospholipid hydroperoxides (PL00H) and ultimately inhibits ferroptosis. (2) Coenzyme Q10 generates its reduced form CoQ10-H2 in the presence of FSP1. (3) GCH1 promotes BH4 biosynthesis reduces phospholipid hydroperoxide accumulation inhibits ferroptosis. (4) DHODH, localized in the mitochondria, oxidizes dihydroorotate (DHO) to orotate (OA) while transferring electrons to ubiquinone in the inner mitochondrial membrane for reduction to ubiquinol.
