Figure 2: Mitochondrial ROS Regulation: From Redox Signaling to Ferroptotic Cell Death.

The mitochondrial electron transport chain (ETC) generates superoxide (O₂•⁻) that is converted to hydrogen peroxide (H₂O₂) by superoxide dismutases (SOD1 in the mitochondrial intermembrane space and SOD2 in the mitochondrial matrix). H₂O₂ serves as a key signaling molecule through redox-dependent cysteine modifications of target proteins. Simultaneously, cellular antioxidant systems regulate ROS levels and prevent oxidative damage. A major antioxidant defense system involves NRF2 activation, which drives NADPH and glutathione (GSH) production. Glutathione peroxidases (GPXs), particularly GPX4, and peroxiredoxins (PRDXs) neutralize H₂O₂ and lipid peroxides. When these protective mechanisms are compromised, excessive ROS can trigger ferroptosis, an iron-dependent cell death pathway. In this process, ferrous iron (Fe²⁺) catalyzes the Fenton reaction, converting H₂O₂ to highly reactive hydroxyl radicals (OH·) that initiate lipid peroxidation of polyunsaturated fatty acids (PUFAs). Multiple protective mechanisms prevent ferroptosis, including: the cystine/glutamate antiporter (Xc⁻) that imports cysteine for GSH synthesis; GPX4 that neutralizes lipid peroxides; ferroptosis suppressor protein 1 (FSP1) that utilizes the Coenzyme Q-NADPH antioxidant system to reduce lipid peroxides independently of GSH; incorporation of monounsaturated fatty acids (MUFAs) that resist peroxidation; and tetrahydrobiopterin (BH4) that acts as a radical-trapping antioxidant. This balanced regulation of ROS determines whether their effects manifest as controlled redox signaling that supports immune function or destructive oxidative damage leading to cell death.