F‐ATP synthase and the permeability transition pore: fewer doubts, more certainties

Whether the mitochondrial permeability transition pore ( PTP ), also called mitochondrial megachannel ( MMC ), originates from the F‐ ATP synthase is a matter of controversy. This hypothesis is supported both by site‐directed mutagenesis of specific residues of F‐ ATP synthase affecting regulation of the PTP / MMC and by deletion of specific subunits causing dramatic changes in channel conductance. In contrast, human cells lacking an assembled F‐ ATP synthase apparently display persistence of the PTP . We discuss recent data that shed new light on this controversy, supporting the conclusion that the PTP / MMC originates from a Ca 2+ ‐dependent conformational change in F‐ ATP synthase allowing its reversible transformation into a high‐conductance channel.