Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore

The mitochondrial permeability transition pore (MPTP) plays a key role in cell death, especially necrosis, and mediates the injury tissues such as the heart and brain experience following ischaemia and reperfusion. However, the molecular identity of the MPTP remains uncertain. Knockout studies have confirmed a role for cyclophilin-D (CyP-D) in pore opening, probably mediated by its peptidyl-prolyl cis-trans isomerase activity that facilitates a conformational change in an inner membrane protein. However, similar knockout studies have cast doubt on the central role of the adenine nucleotide translocase (ANT), previously regarded as a leading contender for the membrane component that forms the transmembrane channel of the MPTP. Here we review the evidence for and against a role for the ANT in MPTP opening and conclude that it usually plays a regulatory role rather than provide the transmembrane pore component. We suggest that the protein fulfilling the latter role is the mitochondrial phosphate carrier (PiC) and summarise recent evidence in support of this proposal. Our data are consistent with a model for the MPTP in which a calcium-triggered conformational change of the PiC, facilitated by CyP-D, induces pore opening. We propose that this is enhanced by an association of the PiC with the “c” conformation of the ANT. Agents that modulate pore opening may act on either or both the PiC and the ANT.