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 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 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.

Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition / Giorgio V.; Burchell V.; Schiavone M.; Bassot C.; Minervini G.; Petronilli V.; Argenton F.; Forte M.; Tosatto S.; Lippe G.; Bernardi P.. - In: EMBO REPORTS. - ISSN 1469-221X. - ELETTRONICO. - 18:7(2017), pp. 1065-1076. [10.15252/embr.201643354]

Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition

Giorgio V.
Primo
;
2017

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 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 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 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.
2017
Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition / Giorgio V.; Burchell V.; Schiavone M.; Bassot C.; Minervini G.; Petronilli V.; Argenton F.; Forte M.; Tosatto S.; Lippe G.; Bernardi P.. - In: EMBO REPORTS. - ISSN 1469-221X. - ELETTRONICO. - 18:7(2017), pp. 1065-1076. [10.15252/embr.201643354]
Giorgio V.; Burchell V.; Schiavone M.; Bassot C.; Minervini G.; Petronilli V.; Argenton F.; Forte M.; Tosatto S.; Lippe G.; Bernardi P.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/794384
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