Mechanism of primary Cd2+-induced rat liver mitochondria dysfunction: discrete modes of Cd2+ action on calcium and thiol-dependent domains |
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Authors: | Belyaeva Elena A Korotkov Sergey M |
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Institution: | a Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez pr.44, 194223, St. Petersburg, Russia |
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Abstract: | We attempted to discern discrete sites of Cd2+ deleterious action on rat liver mitochondrial function. In particular, EGTA, ADP, and cyclosporin A (potent mitochondrial permeability transition antagonists) affected mainly Cd2+ -induced changes in resting state respiration, eliminating its stimulation in KCl medium, while dithiothreitol (DTT, a dithiol reductant) produced its effect both on Cd2+ activation of the basal respiration and Cd2+ depression of uncoupler-stimulated respiration, evoking its restoration. Substantial differences in DTT influence on mitochondrial respiration at low and high Cd2+] were revealed, namely, an enhanced mitochondrial permeabilization in the presence of saturated DTT] at high Cd2+] took place. Besides, DTT only partially reversed Cd2+ -induced swelling in NH4NO3 medium when glutamate plus malate or succinate without rotenone was used. Contrarily, DTT produced complete reversal of the swelling of succinate-energized mitochondria when rotenone was present in the medium. In addition, in the presence of rotenone both Cd2+ -produced activation of the resting state respiration in KCl medium and Cd2+-induced swelling in sucrose medium of succinate-energized mitochondria were more sensitive to cyclosporin A than the same Cd2+ effects obtained on mitochondria oxidizing succinate (without rotenone) or glutamate plus malate. We have concluded that Cd2+, producing primary mitochondrial dysfunction, acts both as a thiol and Me2+ binding site reagent. Suppositions about possible localization of separate sites of direct Cd2+ effects on mitochondrial function were made. |
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Keywords: | Cd2+ action discrete sites Rat liver mitochondrial dysfunction Mitochondrial permeability transition Respiratory chain components Dithiothreitol Cyclosporin A |
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