Mitochondria produce ATP by utilizing about 90% of O2 that is taken up by neurons. During the electron transfer in the inner mitochondrial membrane, electrons
spontaneously leak from the electron transport chain and react with available O2 to produce superoxide. While this superoxide is normally cleared to H2O by superoxide dismutases (e.g., MnSOD in the mitochondria) and glutathione peroxidase in neurons, Ca2+ is accumulated in the cytosol during hypoxic-ischemic injury (see above) and enters into mitochondria, which results in production of mitochondrial free radicals and oxidation of mitochondrial lipid and DNA.49,51,69,89,183,190 Excess Ca2+ in the mitochondria interrupts the electron transport chain and collapses the mito-chondrial membrane potential.194 Therefore, free electrons are accumulated in the mitochondria, which react with oxygen supplied after reperfusion and cause production of superoxide. The superoxide is further processed to produce the hydroxyl radical by a Fenton reaction or peroxynitrite by reacting with nitric oxide. Reactive oxygen and nitrogen species (ROS and RNS) also inhibit the electron transport chain in the mitochondria and amplify generation of mitochondrial free radicals.23,189,210,237,266
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