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 Ca2+-
dependent transformation to form channels with properties
matching those of the permeability transition pore (PTP), a key
player in cell death. The Ca2+ binding site and the mechanism(s)
through which Ca2+ 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
“Ca2+-trigger site” of the PTP to the catalytic site of the F-ATP
synthase b 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 b subunit,
which show a selective decrease in Ca2+-ATP hydrolysis, confer
resistance to Ca2+-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.
