Possible Mechanism for Formation and Regulation of the Palmitate-Induced Cyclosporin A-Insensitive Mitochondrial Pore

Abstract

The mechanism of the palmitate-induced opening of the mitochondrial Ca²⁺-dependent cyclosporin A (CsA)-insensitive pore was studied, as well as the influence on this process of well-known modulators of the CsA-sensitive Ca²⁺-dependent pore. Palmitic acid, which can bind Ca²⁺ with high affinity, induced the CsA-insensitive swelling of mitochondria, whereas palmitoleic and 2-bromopalmitic acids, which have no such affinity for Ca²⁺, failed to induce the pore opening. The palmitate induced Ca²⁺-dependent swelling of mitochondria was not affected by a well-known inhibitor of the CsA-sensitive pore (ADP) and an activator of this pore (inorganic phosphate, P_i). However, this swelling was inhibited by physiological concentrations of ATP ([I]₅₀ = 1.3 mM), but 100 µM ATP increased by 30% the rate of mitochondria swelling if Ca²⁺ had been added earlier. The effects of ATP (inhibition and activation) manifested themselves from different sides of the inner mitochondrial membrane. Mg²⁺ inhibited the palmitate-induced Ca²⁺-dependent swelling of mitochondria with [I]₅₀ = 0.8 mM. It is concluded that palmitic acid induces the opening of the CsA-insensitive pore due to its ability for complexing with Ca²⁺. A possible mechanism of the pore formation and the influence of some modulators on this process are discussed.