F- ATP synthases convert the energy of the transmembrane H+ gradient into ATP with remarkable efficiency [1]. We have recently discovered that in the presence of Ca2+ F- ATP synthases can also form channels with the properties expected of the mitochondrial “permeability transition pore” (PTP) in mammals [2], yeast [3] and drosophila [4]. Ca2+-dependent PTP opening causes a large increase of permeability of the inner mitochondrial membrane, which has long been known to dissipate ion gradients and to cause detrimental effects on mitochondrial and cell function [5]. Our results show that channel activity can be seen in reconstituted systems with highly purified F- ATP synthases, indicating that channel formation must occur within the enzyme complex. I will present our recent results on the mechanism of channel formation, as studied by site directed mutagenesis of key regulatory residues of F- ATP synthases, and on the development of new inhibitors.