Fig. 2

Sources of reactive oxygen species (ROS) in mitochondria. The activity of the electron transport chain generates a relatively small flux of ROS under normal conditions, but its production can be greatly magnified by events occurring during ischemia and reperfusion. Complex I (NADH dehydrogenase) and complex III (coenzyme Q (CoQ) and cytochrome C oxidoreductase) produce superoxide (O₂^-), which leads to hydrogen peroxide (H₂O₂) formation by spontaneous dismutation or via the enzymatic action of manganese superoxide dismutase (MnSOD). In the presence of transition metals, H₂O₂ can form the highly reactive hydroxyl radical (OH^•) superoxide can also interact with nitric oxide (NO) to form reactive nitrogen oxide species such as peroxynitrite (ONOO^-), which produce cellular dysfunction by S-nitrosylating proteins. ROS generated by complex I are released into the mitochondrial matrix, while superoxide produced by complex III can occur in both the mitochondrial matrix and the intermembrane space between the outer and inner mitochondrial membranes. Other sources of mitochondrial superoxide are enzymes glycerol-3-phosphate dehydrogenase (G3PD), the growth factor adaptor p66Shc, and NADPH oxidase-4 (Nox4). ß-oxidation of fatty acids can also result in mitochondrial superoxide generation secondary to oxidation of electron transferring protein (ETF) by the catalytic activity of the electron transferring flavoprotein ubiquinone oxidoreductase (ETF-QOR), another enzyme expressed on the mitochondrial inner membrane. Monoamine oxidase (MAO), which is localized to the outer mitochondrial membrane, catalyzes the formation of H₂O₂ secondary to catecholamine metabolism. Not depicted are the mitochondrial enzymes aconitase and dihydroorotate, which can produce superoxide, but their role in ischemia/reperfusion is uncertain.The mitochondrial anion carrier, uncoupling protein-2 (UCP2), functions to separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, a phenomenon referred to as the mitochondrial proton leak. UCP2 acts to facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Although it was originally thought to play a role in nonshivering thermogenesis, obesity, diabetes and atherosclerosis, it now appears that the main function of UCP2 is the control of mitochondria-derived ROS.