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.
Belyaeva
Elena A
EA
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez pr. 44, 194223, St.-Petersburg, Russia. belyaeva@iephb.ru
Glazunov
Vadim V
VV
Korotkov
Sergey M
SM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D003992:Dibucaine / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000187:drug effects / Q000502:physiology*; D014450:Electron Transport Complex III / Q000187:drug effects / Q000502:physiology*; D005033:Ethylmaleimide / Q000494:pharmacology; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D009840:Oligomycins / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D012430:Ruthenium Red / Q000494:pharmacology
D009840:Oligomycins; D002104:Cadmium; D012402:Rotenone; D012430:Ruthenium Red; D000244:Adenosine Diphosphate; D002374:Catalase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D003992:Dibucaine; D005033:Ethylmaleimide; D002118:Calcium