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 Pi 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 Pi 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.