Mitochondrial models of pathologies with oxidative stress. Efficiency of alkalization to reduce mitochondrial damage.
Previously, we developed a method to monitor the development of oxidative stress in isolated liver mitochondria. The method is based on recording of membrane potential changes in response to sequential introduction of low concentrations (5-20 μM) of tert-butyl hydroperoxide (tBHP). It allows monitoring of the extent of amplification or attenuation of oxidative stress caused by external influences (changes in incubation conditions, additions of biologically active substances). Based on this method, we created a mitochondrial model for the study and improvement of treatment of pathologies associated with oxidative stress. The following two processes were simulated in the experiments: 1) introduction of desferal for treatment of serious diseases caused by cell overload with iron (high desferal concentrations were shown to suppress mitochondrial energetics); 2) efficiency of alkalization to reduce mitochondrial damage induced by oxidative stress. The experiments have shown that even a small increase in pH (alkalization) increases the amount of tBHP that can be added to mitochondria before the MPTP ("mitochondrial permeability transition pore") is induced. The effect of alkalization was shown to be close to the effect of cyclosporin A in the pH range 7.2-7.8. The mechanism of the similarities of these effects in the organism and in mitochondrial suspensions is explained by the increase in toxic reactive oxygen species in both systems under oxidative stress.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. nfedotcheva@mail.ru.
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Fedotcheva
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Mokhova
D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D005290:Ferric Compounds; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C024823:ferric sulfate; D020122:tert-Butylhydroperoxide; D004492:Edetic Acid; D003676:Deferoxamine