Figure 3
From: Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney
Influence of NO and O2 on mitochondria activity. The mitochondrial electron transport chain includes four multiple subunit enzyme complexes of proteins (complexes I–IV), ATP synthase (complex V), and the adenine nucleotide translocator (ANT). Electrons are collected at the complexes I (NADH dehydrogenase) and II (succinate dehydrogenase) after oxidation of nicotinamide adenine dinucleotide (NADH) and of succinate, respectively, is transferred to coenzyme Q (CoQ) to give reduced CoQ. Electrons from reduced CoQ are transferred first to complex III (cytochrome bc1), then to cytochrome c (cyt c) and followed by complex IV (cytochrome c oxidase, COX), and finally to oxygen (O2) to give water (H2O). An electrochemical gradient is generated between the mitochondrial matrix and the intermembrane space by pumping protons through the inner membrane using the energy generated by the electron flow. This electrochemical gradient is then used to reintroduce protons through the complex V (ATP synthase) and to convert inorganic phosphate and ADP to ATP. The ATP, generated in mitochondria, is then exchanged for cytosolic ADP by the ANT. With increase in NO/O2 ratio, NO competitively inhibits complex IV associated with an electron leakage of the complexes chain and finally favors the generation of superoxide anions (O2−•). Hydrogen peroxide (H2O2) generated from O2−• by superoxide dismutase (SOD) contributes to hypoxia adaptation response via stabilization of HIF-α. If prolonged production of O2−• overwhelms capacity of the mitochondrial’s antioxidant system including the superoxide dismutase (MnSOD) and glutathione peroxidase (GSHpx), formation of large amount of peroxynitrite (ONOO-) and H2O2, precursor of the hydroxyl radical (OH•), via the Fenton reaction occurs. Peroxynitrite further inhibits the mitochondrial Mn-superoxide dismutase by nitration. Cytosolic (xanthine oxydase and cytochrome P450 reductases, and NOS, myeloperoxidase) and membrane (NADPH oxidase, the cytochrome P450) intramitochondrial ROS overproduction leads to cell necrosis or apoptosis.