Mitochondrial ROS generation, neutralization, macromolecular damage and repair. A. Superoxide (O2•-) is generated in the mitochondrial matrix or inner membrane space (IMS) when an electron is donated to O2 (shown for complex I and III here). Superoxide produced in the IMS is converted to H2O2 by Cu/Zn superoxide dismutase (CuZnSOD). Superoxide produced in the matrix is converted to H2O2 by Mn superoxide dismustase (MnSOD). H2O2 can be neutralized to H2O through the action of the glutathione peroxidase (GPX)/glutathione reductase (GR) cycle at the expense of reducing equivalents (NADPH) (reduced glutathione = GSH; oxidized glutathione = GSSG). H2O2 may also be converted to H2O by peroxiredoxin (Prx), coupled to the oxidation of reduced thioredoxin (Trx). Oxidized Trx is reduced by thioredoxin reductase (TrxR) at the expense of reducing equivalents (nicotinamide adenine dinucleotide phosphate, NADPH). H2O2 can also diffuse into the cytosol, where it is neutralized to H2O by catalase (CAT) or other cytosolic enzymes (not shown). Superoxide in the matrix or IMS can form other ROS, such as peroxynitrite (ONOO-). H2O2 may also form other ROS, such as hydroxyl radicals (•OH). B. ROS produced by mitochondria can damage nuclear and mitochondrial DNA, causing lesions, including base modifications. These effects are countered by a variety of DNA repair processes, including the base excision repair pathway. C. ROS generated by mitochondria may damage cytosolic proteins. Heat shock proteins (Hsps) interact with misfolded proteins and assist in returning proteins to their native structure. Alternatively, damaged proteins can be ubiquitinated (Ub) and degraded by proteasomes. D. ROS generated by mitochondria can damage membrane phospholipid fatty acids via peroxidation reactions. Note that, for the purpose of clarity, this figure omits and/or simplifies some pathways involved in mitochondrial ROS metabolism.