REGULATION OF THE PERMEABILITY TRANSITION PORE, A VOLTAGE-DEPENDENT MITOCHONDRIAL CHANNEL INHIBITED BY CYCLOSPORINE-A

Mitochondria from a variety of sources possess a regulated inner membr ane channel, the permeability transition pore (MTP), which is responsi ble for the 'permeability transition', a sudden permeability increase to solutes with molecular masses less than or equal to 1500 Da, most e asily observed after Ca2+ accumulation. The MTP is a voltage-dependent channel blocked by cyclosporin A with K-i in the nanomolar range. The MTP open probability is regulated by both the membrane potential and matrix pH. The probability of pore opening increases as the membrane i s depolarized, while it decreases as matrix pH is decreased below 7.3 through reversible protonation of histidine residues. Many physiologic al and pathological effecters, including Ca2+ and ADP, modulate MTP op eration directly through changes of the gating potential rather than i ndirectly through changes of the membrane potential (Petronilli, V., C ola, C., Massari, S., Colonna, R. and Bernardi, P. (1993) J. Biol. Che m. 268, 21939-21945). Here we present recent work from our laboratory indicating that (i) the voltage sensor comprises at least two vicinal thiols whose oxidation-reduction state affects the MTP gating potentia l; as the couple becomes more oxidized the gating potential increases; conversely, as it becomes more reduced the gating potential decreases ; (ii) that MTP opening is fully reversible, as mitochondria maintain volume homeostasis through several cycles of pore opening/closure; and (iii) that the mechanism of MTP inhibition by cyclosporin A presumabl y involves a mitochondrial cyclophilin but does not utilize a calcineu rin-dependent pathway.