FROM CALCIUM SIGNALING TO CELL-DEATH - 2 CONFORMATIONS FOR THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE - SWITCHING FROM LOW-CONDUCTANCE TO HIGH-CONDUCTANCE STATE

The permeability transition pore (PTP) is a channel of the inner mitoc hondrial membrane that appears to operate at the crossroads of two dis tinct physiological pathways, i.e., the Ca2+ signaling network during the life of the cell, and the effector phase of the apoptotic cascade during Ca2+-dependent cell death. Correspondingly, two open conformati ons of the PTP can also be observed in isolated organelles. A low-cond uctance state, that allows the diffusion of small ions like Ca2+, is p H-operated, promoting spontaneous closure of the channel. A high-condu ctance state, that allows the unselective diffusion of big molecules, stabilizes the channel in the open conformation, disrupting in turn th e mitochondrial structure and causing the release of proapoptotic fact ors. Our current results indicate that switching from low- to high-con ductance state is an irreversible process that is strictly dependent o n the saturation of the internal Ca2+-binding sites of the PTP. Thus, the high conductance state of the PTP, which was shown to play a pivot al role in the course of excitotoxic and thapsigargin-induced cell dea th, might result from a Ca2+-dependent conformational shift of the low -conductance state, normally participating in the regulation of cellul ar Ca2+ homeostasis as a pH-operated channel. These observations lead us to propose a simple biophysical model of the transition between Ca2 + signaling and Ca2+-dependent apoptosis. (C) 1998 Elsevier Science B. V. All rights reserved.