Channel formation from F-ATP synthase: Role of subunit f

The Permeability transition pore (PTP) is a mitochondrial channel the opening of which induces cell death. The molecular nature of the PTP has long remained a mystery. We proposed that dimers of F-ATP synthase form the PTP, but how this Ca2+-dependent transition may occur and which subunits are directly involved in its formation and regulation are an open issue. Structural data suggest an important role of f subunit in dimer stabilization in Yarrowia lipolytica and Saccharomyces Cerevisiae and so we focused on this subunit as a possible pore-forming site. We generated human cells lacking, or with a decreased level of, the f subunit. We found that low expression of f subunit does not affect mitochondrial respiration or F-ATP synthase subunit stoichiometry, but it destabilizes dimer formation, affects cristae morphology and desensitizes PTP opening. This last feature was confirmed with electrophysiological studies on f-null cells, which display a PTP of lower conductance. These data suggest that the PTP forms at the interface between F-ATP synthase monomers and involves subunit f.