FOF1-ATP Synthase Dimers and The Mitochondrial Permeability Transition Pore from Yeast to Mammals

The mitochondrial permeability transition pore (PTP) is a voltage-dependent channel that allows solutes of molecular mass ≤ 1.5 kDa to equilibrate across the inner membrane. Matrix Ca2+ accumulation, together with Pi and a set of compounds collectively called “inducers”, is necessary to induce PTP opening. In mammals cyclosporin (Cs) A desensitizes the PTP through its binding to cyclophilin D, a matrix protein that facilitates PTP opening. Yeast and Drosophila mitochondria also possess Ca2+-activated channels which, at variance from the mammalian PTP, are insensitive to CsA and inhibited rather than activated by Pi. We show (i) that the permeability properties of the Drosophila channel, which displays selectivity toward Ca2+ and H+, are not modified by expression of human cyclophilin D; and (ii) that, in keeping with our recent demonstration that the mammalian PTP forms from dimers of the FOF1-ATP synthase, Ca2+-dependent currents can be elicited in reconstitution experiments with purified dimers of the yeast enzyme. We are currently investigating the effect of genetic ablation of FOF1-ATP synthase subunits that mediate dimerization on PTP opening in yeast, Drosophila and mammalian mitochondria. Our findings suggest that the PTP-forming ability of FOF1-ATP synthase has been conserved in evolution, and that the channels display species-specific features.