Mitochondrial Permeability Transition Pore

The mitochondrial permeability transition (PT) is a Ca 2+ -dependent increase of mitochondrial inner membrane permeability to solutes with molecular masses up to about 1500 Da. Its occurrence is always accompanied by depolarization, while onset of matrix swelling, depletion of matrix pyridine nucleotides, outer membrane rupture, and release of intermembrane proteins including cytochrome c depend on the open time. The PT is due to the reversible opening of a high-conductance, voltage-dependent channel in the inner mitochondrial membrane, the PT pore (PTP). In spite of many efforts, its molecular identity remains unknown. In this review, which is limited to the PTP of mammals, the essential aspects of its pathophysiology, with specific emphasis on regulation by matrix cyclophilin D, the mitochondrial target of cyclosporin A; modulation by Me 2+ ions, the proton electrochemical gradient and redox effectors; consequences of pore opening as a key to understand its role in cell dysfunction and death; involvement in kinase signaling pathways; and potential role in Ca 2+ homeostasis are discussed. From this analysis, the PTP emerges as a viable target for therapeutic intervention in cancer and degenerative diseases.