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

Giorgio, Valentina ; Burchell, Victoria ; Schiavone, Marco ; Bassot, Claudio ; Minervini, Giovanni ; Petronilli, Valeria ; Argenton, Francesco ; Forte, Michael ; Tosatto, Silvio ; Lippe, Giovanna ; Bernardi, Paolo

EMBO reports, 2017-07, Vol.18 (7), p.1065-1076 [Periódico revisado por pares]

Hoboken: John Wiley and Sons Inc

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  • Título:
    Ca2+ binding to F‐ATP synthase β subunit triggers the mitochondrial permeability transition
  • Autor: Giorgio, Valentina ; Burchell, Victoria ; Schiavone, Marco ; Bassot, Claudio ; Minervini, Giovanni ; Petronilli, Valeria ; Argenton, Francesco ; Forte, Michael ; Tosatto, Silvio ; Lippe, Giovanna ; Bernardi, Paolo
  • Assuntos: ATP synthase ; calcium ; channels ; mitochondria ; permeability transition ; Scientific Report ; Scientific Reports
  • É parte de: EMBO reports, 2017-07, Vol.18 (7), p.1065-1076
  • Notas: These authors contributed equally to this work
  • Descrição: 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. Synopsis In response to Ca2+ ions mitochondria can undergo a permeability transition (PT). This study provides evidence that Ca2+‐binding to the catalytic β subunit of F1F0 ATPase 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 Ca2+ binding to T163 of F‐ATP synthase β subunit, which in physiological catalysis coordinates Mg2+. Ca2+ 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 Mg2+‐ATPase and inhibits Ca2+‐ATPase activity, prevents PT‐dependent HeLa cells death and lowers incidence of apoptosis in developing zebrafish embryos. In response to Ca2+ ions mitochondria can undergo a permeability transition (PT). This study provides evidence that Ca2+‐binding to the catalytic β subunit of F1F0 ATPase induces a conformational change that triggers pore opening.
  • Editor: Hoboken: John Wiley and Sons Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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