Abstract
F-ATP synthases convert the electrochemical energy of the H(+) gradient into the chemical energy of ATP with remarkable efficiency. Mitochondrial F-ATP synthases can also undergo a Ca(2+)-dependent transformation to form channels with properties matching those of the permeability transition pore (PTP), a key player in cell death. The Ca(2+) binding site and the mechanism(s) through which Ca(2+) can transform the energy-conserving enzyme into a dissipative structure promoting cell death remain unknown. Through in vitro, in vivo and in silico studies we (i) pinpoint the "Ca(2+)-trigger site" of the PTP to the catalytic site of the F-ATP synthase β subunit and (ii) define a conformational change that propagates from the catalytic site through OSCP and the lateral stalk to the inner membrane. T163S mutants of the β subunit, which show a selective decrease in Ca(2+)-ATP hydrolysis, confer resistance to Ca(2+)-induced, PTP-dependent death in cells and developing zebrafish embryos. These findings are a major advance in the molecular definition of the transition of F-ATP synthase to a channel and of its role in cell death.