From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state.

The permeability transition pore (PTP) is a channel of the inner mitochondrial membrane that appears to operate at the crossroads of two distinct 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 conformations of the PTP can also be observed in isolated organelles. A low-conductance state, that allows the diffusion of small ions like Ca2+, is pH-operated, promoting spontaneous closure of the channel. A high-conductance state, that allows the unselective diffusion of big molecules, stabilizes the channel in the open conformation, disrupting in turn the mitochondrial structure and causing the release of proapoptotic factors. Our current results indicate that switching from low- to high-conductance state is an irreversible process that is strictly dependent on 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 pivotal role in the course of excitotoxic and thapsigargin-induced cell death, might result from a Ca2+-dependent conformational shift of the low-conductance state, normally participating in the regulation of cellular 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.