Calcium binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition

F-ATP synthases convert the electrochemical energy of the proton gradient into the chemical energy of ATP with remarkable efficiency. Mitochondrial F-ATP synthases can also undergo a calcium-dependent transformation to form channels with properties matching those of the permeability transition pore (PTP), a key player in cell death. The calcium binding site, and the mechanism(s) through which calcium 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 have (i) pinpointed the “calcium-trigger site” of the PTP to the catalytic site of the F-ATP synthase β subunit and (ii) defined 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 calcium-ATP hydrolysis, confer resistance to calcium-induced, PTP-dependent death in cells and developing zebrafish embryos.