Cd2+ versus Ca2+-produced mitochondrial membrane permeabilization: a proposed direct participation of respiratory complexes I and III

A comparison of Cd²⁺ and Ca²⁺ effects on in vitro rat liver mitochondria function and a further study of their interaction were conducted. Similarity and distinction in action of rotenone, oligomycin, N-ethylmaleimide, dithiothreitol, catalase, dibucaine, ruthenium red, cyclosporin A (CsA), and ADP on Cd²⁺ and/or Ca²⁺-induced mitochondrial dysfunction were revealed. We found that rotenone exerted a strong protective action both against Ca²⁺ and Cd²⁺-produced mitochondrial membrane permeabilization (MMP). In contrast to Ca²⁺, catalase and dibucaine did not influence on main Cd²⁺ effects. In NH₄NO₃ medium N-ethylmaleimide (NEM) at low concentrations increased markedly Cd²⁺-produced swelling of non-energized mitochondria, whereas it exhibited a partial reversal effect following energization. In sucrose medium low [NEM] did not change Cd²⁺-produced mitochondrial swelling. High [NEM] promoted synergistic increase of the Cd²⁺-produced swelling in NH₄NO₃ medium; all above effects were reversed (and prevented) by dithiothreitol, DTT. We shown also that when exogenous Ca²⁺ and P_i were simultaneously present in NH₄NO₃ medium, DTT reversed only partially Cd²⁺-produced swelling of succinate plus rotenone-energized mitochondria, while DTT recovery action was complete when either Ca²⁺ or P_i were separately administered to the Cd²⁺-treated mitochondria. Besides, DTT added following a low Cd²⁺ pulse in KCl medium containing exogenous Ca²⁺ induced a substantial enhancing of sustained Cd²⁺ stimulation of mitochondrial basal respiration and the stimulation was CsA-sensitive, while the activation promoted by low [Cd²⁺] alone was totally eliminated by DTT supplement. We observed the similar respiratory activation earlier when high concentrations of Cd²⁺ in the absence of added Ca²⁺ were used but it was completely CsA-insensitive. A possible involvement of respiratory chain components, namely complex I (P-site) and complex III (S-site) in Cd²⁺and/or Ca²⁺-produced MMP was discussed.