INHIBITORS OF ADP ATP-ANTIPORTER INDUCE 2 CA2+-DEPENDENT UNCOUPLING PATHWAYS IN RAT-LIVER MITOCHONDRIA/

The effect of the ADP/ATP-antiporter inhibitor carboxyatractylate on t he inner mitochondrial membrane permeability was studied. Carboxyatrac tylate was found to induce two uncoupling pathways: the Ca2+-dependent permeability transition pore and another system which is sensitive to the inhibitor of the Ca2+ uniporter Ruthenium Red (apparently involvi ng Ca2+ recycling). The level of Ca2+-recycling induction correlates w ith the size of the fraction of the mitochondrial population that has undergone permeabilization-resealing; prevention of permeabilization b y cyclosporin A results in inhibition of induction of Ca2+-recycling. This suggests that the primary effect of carboxyatractylate binding to mitochondria is the induction of the permeability transition pore, an d Ca2+-recycling is induced as a consequence. Both pathways are induce d by carboxyatractylate concentrations specific for the ADP/ATP-antipo rter. The data suggest that the ADP/ATP-antiporter is directly involve d in the formation of the permeability transition pore of the mitochon drial inner membrane.