FIGURE 13.

Role of CoQ in ferroptosis regulation. Ferroptosis suppressor protein 1 (FSP1) acts as an oxidoreductase mainly localized on the plasma membrane and reduces CoQ to CoQH₂ using electrons from reduced nicotinamide adenine dinucleotide (NADH) or reduced nicotinamide adenine dinucleotide phosphate (NADPH). By directly scavenging lipid peroxy radicals (LOO^•) generated from lipid peroxidation, the fully reduced form of CoQ, CoQH₂, prevents excessive lipid peroxidation and thus inhibits ferroptosis. In the cytosol and mitochondria, glutathione peroxidase 4 (GPX4) converts glutathione (GSH) to oxidized glutathione (GSSG) while reducing lipid hydroperoxides (LOOH) to lipid alcohols (LOH), which is the main mechanism to regulate ferroptosis. Mitochondrial ROS production likely contributes to ferroptosis. On the other hand, CoQH₂ generation from respiration and other dehydrogenases such as dihydroorotate dehydrogenase (DHODH) and glycerol-3-phosphate dehydrogenase (GPDH) likely enhance defense against ferroptosis by inhibiting lipid peroxidation. See glossary for other abbreviations.