Cyclosporin A-sensitive permeability transition pore is involved in Cd2+-induced dysfunction of isolated rat liver mitochondria: doubts no more

There is dose-dependent Cd2+-evoked swelling of isolated rat liver mitochondria energized by complex I, II, or IV respiratory substrates in sucrose medium in the absence of added Ca2+ and Pi, which is prevented by Sr2+. Permeability transition effectors (ADP, CsA, EGTA, RR, DTT, ATR, Pi, and Ca2+) affect in a corresponding way Cd2+-promoted membrane permeabilization in NH4NO3, KCl, and sucrose media. Maximal depression of Cd2+-induced swelling is achieved by simultaneous addition of ADP, Mg2+, and CsA that produces either synergistic (NH4NO3) or additive (KCl and sucrose media) action. Sustained activation by low [Cd2+] of mitochondrial basal respiration in KCl medium is observed both in the absence and in the presence of rotenone and/or oligomycin but only in the latter case (rotenone + oligomycin) CsA inhibits completely Cd2+ activation of St 4 respiration and partially reverses DNP-uncoupled respiration depressed by cadmium. Cd2+ effects are discussed in terms of comparison with those of Zn2+ and PhAsO.