What Makes You Can Also Break You, Part II: Mitochondrial Permeability Transition Pore Formation by Dimers of the F1FO ATP-Synthase?

view of mPT formation, providing evidence that cypD targets the OSCP subunit of the lateral stalk. Moreover, in addition to presenting a series of biochemical and functional evidence indicating that the mPT is correlated with the cypD-OSCP interaction, they directly addressed the pore forming ability of purified F 1 F O ATP-synthases. It is well established that the mPT represents the opening of a high-conductance channel, called the “mitochondrial megachannel” (MMC), identified by patch-clamping the inner membrane (Kinnally et al., 1989; Petronilli et al., 1989; Szabó et al., 1992; De Marchi et al., 2006). Intriguingly, now Giorgio et al. (2013) show that by incorporating purified F 1 F O ATP-synthase dimers in liposomes, electrophysiological recordings identical to the MMC can be obtained. Whilst these results provide the most direct evidence so far for mPT pore formation by the F 1 F O ATP-synthase, again, they raise a series of new questions. First, in order to obtain a reversible ion permeable pore at the dimerization interface of a membrane protein dimer, two hydrophobic surfaces should be able to provide a hydrophilic lining while the pore is assembled in order to allow ion flow. Then, when the channel is inactivated, these surfaces should become hydrophobic again when the dimer is disassembled, to allow interaction with membrane lipids. In theory, this could be achieved by rotation of amphipathic alpha-helices. If the interpretations of Giorgio et al. are correct, such a helix should be present at the surface of the F 1 F O ATP-synthase, precisely at the site where two ATP-synthases interact to form the dimers. Unfortunately, there is insuffiA commentary on