Regulation of the mitochondrial permeability transition pore by ubiquinone analogs. A progress report

Abstract

The permeability transition pore (PTP) is a mitochondrial inner membrane Ca2+-sensitive channel that plays a key role in different models of cell death. In a series of recent studies we have shown that the PTP is modulated by quinones, and we have identified three functional classes: (i) PTP inhibitors; (ii) PTP inducers; and (iii) PTP-inactive quinones that compete with both inhibitors and inducers. Here, we review our current understanding of pore regulation by quinones, and present the results obtained with a new series of structural variants. Based on the effects of the compounds studied so far, we confirm that minor structural changes profoundly modify the effects of quinones on the PTP. On the other hand, quinones with very different structural features may have qualitatively similar effects on the PTP. Taken together, these results support our original proposal that quinones affect the PTP through a common binding site whose occupancy modulates its open-closed transitions, possibly through secondary changes of the Ca2+-binding affinity.