Aluminum as an inducer of the mitochondrial permeability transition

Treatment of rat liver mitochondria with aluminum in the presence of Ca2+ r esults in large amplitude swelling accompanied by loss of endogenous Mg2+ a nd K+ and oxidation of endogenous pyridine nucleotides. The presence of cyc losporin A, ADP, bongkrekic acid, N-ethylmaleimide and dithioerythritol pre vent these effects, indicating that binding of aluminum to the inner mitoch ondrial membrane, most likely at the level of adenine nucleotide translocas e, correlates with the induction of the membrane permeability transition (M PT). Indeed, aluminum binding promotes such a perturbation at the level of ubiquinol-cytochrome c reductase, which favors the production of reactive o xygen species. These metabolites generate an oxidative stress involving two previously defined sites in equilibrium with the glutathione and pyridine nucleotides pools, the levels of which correlate with the increase in MPT i nduction. Although the above-described phenomena are typical of MPT, they a re not paralleled by other events normally observed in response to treatmen t with inducers of MPT (e.g., phosphate), such as the collapse of the elect rochemical gradient and the release of accumulated Ca2+ and oxidized pyridi ne nucleotides. Biochemical and ultrastructural observations demonstrate th at aluminum induces a pore opening having a conformation intermediate betwe en fully open and closed in a subpopulation of mitochondria. While inorgani c phosphate enhances the MPT induced by ruthenium red plus a deenergizing a gent, aluminum instead inhibits this phenomenon. This finding suggests the presence of a distinct binding site for aluminum differing from that involv ed in MPT induction.