Mechanism of primary Cd2+-induced rat liver mitochondria dysfunction: discrete modes of Cd2+ action on calcium and thiol-dependent domains.
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.
Belyaeva
Elena A
EA
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez pr44, 194223, St. Petersburg, Russia. belyaeva@EB10330.spb.edu
Korotkov
Sergey M
SM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002105:Cadmium Poisoning / Q000473:pathology*; D002118:Calcium / Q000502:physiology*; D002588:Cesium Radioisotopes / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000502:physiology*; D014475:Uncoupling Agents / Q000494:pharmacology
D002588:Cesium Radioisotopes; D002614:Chelating Agents; D013438:Sulfhydryl Compounds; D014475:Uncoupling Agents; D002104:Cadmium; D012402:Rotenone; D004533:Egtazic Acid; D000244:Adenosine Diphosphate; D002118:Calcium