Neuropharmacology & Neurotherapeutics
Azathioprine
Apr. 18, 2021
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Mitochondrial reactive oxygen species generation and antioxidant defense systems
The Complex I flavin (CIF ) and ubiquinone (CIQ ) sites, the Complex II flavin site (CIIF ), and Complex IIIQo (CIIIQ0) are sites of the electron-transport-chain components that generate superoxide anions. Other sources of superoxide include enzymatic reactions that transfer electrons to the electron transport chain (eg, mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), and the last step of β-oxidation, electron-transferring flavoprotein ubiquinone oxidoreductase (ETFQOR), pyruvate dehydrogenase (PDH), 2-oxoglutarate dehydrogenase (OGDH), and branched-chain 2-oxoacid dehydrogenase (BCKDH)). Superoxide generated in the mitochondrial matrix by these sites is converted to hydrogen peroxide by manganese-dependent superoxide dismutase 2 (SOD2). Moreover, in response to stress, p66Shc (which functions in the intracellular pathways that convert oxidative signals into apoptosis) translocates to mitochondria to directly stimulate hydrogen peroxide generation by transferring electrons to cytochrome c. Hydrogen peroxide is further inactivated using the reducing equivalents of NADPH by mGSH/Gpx or Prx3/Trx2 antioxidant systems, yielding water. Legend: CIF = Complex I flavin site, CIQ = Complex I ubiquinone site, CIIF = Complex II flavin site, CIIIQ0 = Complex IIIQo, GPX1 = glutathione peroxidase, GR = GSSG-reductase, PRX3 = peroxiredoxin 3, SOD2 = superoxide dismutase 2, TRX2 = thioredoxin-2, TrxRD = thioredoxin reductase. (Source: Ribas V, GarcÃa-Ruiz C, Fernández-Checa JC. Glutathione and mitochondria. Front Pharmacol 2014;5:151. Creative Commons Attribution license.)