It is known that several divalent cations induce the mitochondrial permeability transition (MPT) that accompanied with opening the MPT pore, Ca2+ release from the mitochondria and swelling of these organelles. Such processes frequently lead to the cell damage and death. Nevertheless the characteristics of the metal-induced MPT remain elusive. The aim of this research was to compare the molecular mechanisms of the Ca2+ (5.0-100.0 μM)-, Cd2+ (0.1-50.0 μM)- and Zn2+ (0.1-7.0 μM)-induced MPT. The experiments were performed on the isolated mitochondria obtained from outbred adult rat liver by differential centrifugation (1). The animals were anesthetized by inhalation with diethyl ether and decapitated. Mitochondrial swelling was measured using spectrophotometer and analyzed by: i) maximal rate; ii) lag time; iii) peak amplitude (changes of the mitochondrial volume). Ca2+ release from the mitochondria was investigated using Ca2+-selective electrode and analyzed by: i) maximal rate; ii) duration; iii) peak amplitude (concentration of released Ca2+). Cyclosporin A (10 μM), dithiothreitol (1 mM), 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1 mM) and 7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (1 μM) were used as modulators of the metal-induced MPT. The concentration of mitochondrial protein was measured by Lowry method (2). We showed, that the metal-induced MPT is mediated by megachannel activation and involves cyclophilin D. Carboxyl groups of the potential-dependent anion channel contribute to the metal-induced MPT. Sulfhydryl groups of the ADP/ATP-antiporter are involved in the Cd2+- and Zn2+-induced MPT. Binding of Ca2+ and Zn2+ with cyclophilin D and Cd2+ – with ADP/ATP-antiporter represents key events for the activation of the MPT pore. Mitochondrial Na+/Ca2+-exchanger stimulates the metal-induced MPT. In general, it was discovered different mechanisms of the Ca2+-, Cd2+- and Zn2+-induced MPT, swelling of mitochondria and Ca2+ release from them under the influence of these cations and also the MPT initiated by low and high concentrations of Ca2+. We believe that the obtained differences depend on the ability of cations to interact with constituents of the MPT pore and on the functional state of other transporting systems of these organelles. Thus, as a result of our investigations the molecular mechanisms of the interaction of Ca2+, Cd2+ and Zn2+ with the MPT pore were determined and compared.