The Mitochondrial Permeability Transition Pore: Past, Present, and Future

The mitochondrial permeability transition (PT) is a Ca2+-dependent permeability increase of the inner mitochondrial membrane mediated by opening of a high-conductance channel, the PT pore. Its molecular nature has been the subject of intense research and the source of controversies, but a considerable consensus has been reached that the PT originates from specific conformations of the F_OF₁-ATP synthase and of the adenine nucleotide translocator. The ATP synthase forms high-conductance channels in mammals and yeast but not in the anoxia- and salt-tolerant brine shrimp Artemia franciscana, which is refractory to the PT; it forms low-conductance and Ca2+-selective channels in Drosophila melanogaster, which undergoes a process of Ca2+-induced Ca2+ release but not a PT. The structural definition of ATP synthases from several species may allow for some inferences to be made about the mechanism of channel formation, or lack thereof, and provides a testable framework for future research.