Ca 2+ binding to F‐ATP synthase β subunit triggers the mitochondrial permeability transition

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. image In response to Ca 2+ ions mitochondria can undergo a permeability transition ( PT ). This study provides evidence that Ca 2+ ‐binding to the catalytic β subunit of F 1 F 0 ATP ase induces a conformational change that is transduced to the OSCP subunit and the lateral stalk to induce pore opening. Onset of the PT depends on Ca 2+ binding to T163 of F‐ ATP synthase β subunit, which in physiological catalysis coordinates Mg 2+ . Ca 2+ binding to the catalytic site may induce a conformational change that is transmitted to the peripheral stalk through OSCP , leading to the PT . A T163S mutation increases Mg 2+ ‐ ATP ase and inhibits Ca 2+ ‐ ATP ase activity, prevents PT ‐dependent HeLa cells death and lowers incidence of apoptosis in developing zebrafish embryos.