Control of the mitochondrial permeability transition pore by high-affinity ADP binding at the ADP/ATP translocase in permeabilized mitochondria.

Low levels of ADP binding at the ADP/ATP translocase caused inhibition of the Ca2+-induced permeability transition of the mitochondrial inner membrane, when measured using the shrinkage assay on mitochondria, which have already undergone a transition. Inhibition was prevented by carboxyatractyloside, but potentiated by bongkrekic acid, which increased the affinity for inhibition by ADP. This suggests that inhibition was related to the conformation of the translocase. Ca2+ addition was calculated to remove most of the free ADP. Ca2+ added after ADP induced a slow decay of the inhibition, which probably reflected the dissociation of ADP from the translocator. We conclude that the probability of forming a permeability transition pore (PTP) is much greater when the translocase is in the CAT conformation than in the BKA conformation, and, in the absence of CAT and BKA, the translocator is shifted between the BKA and CAT conformations by ADP binding and removal, even in deenergized mitochondria with no nucleotide gradients.