Tyramine and monoamine oxidase inhibitors as modulators of the mitochondrial membrane permeability transition

Incubation of rat liver mitochondria with 100-500 muM tyramine, a substrate for monoamine oxidases A and B (MAOs), in the presence of 30 muM Ca2+ induces matrix swelling, accompanied by collapse of membrane potential, efflux of endogenous Mg2+ and accumulated Ca2+ and oxidation of endogenous pyridine nucleotides. These effects are completely abolished in the presence of cyclosporin A, ADP, dithioerythritol and N-ethylmaleimide, thus confirming the induction of the mitochondrial membrane permeability transition (MPT). The observed partial protective effect exerted by catalase indicates the involvement of both MAO-derived hydrogen peroxide and aldehyde. Higher concentrations of tyramine (1-2 mm) are less effective or even completely ineffective. At these high concentrations tyramine has an inhibitory effect when the MPT is induced by 100 muM Ca2+. The MAO inhibitors clorgyline (50 muM) and pargyline (500 muM) completely protect against MPT induction by 100 muM tyramine but also inhibit the phenomenon, although with different efficacy, when it is induced by 100 muM Ca2+ in the absence of tyramine. Taken together, our data suggest that tyramine, clorgyline and pargyline act as modulators of the MPT either through a direct inducing/protective effect or by controlling hydrogen peroxide and aldehyde generation.