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

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

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1065-1076
Number of pages12
JournalEMBO Reports
Volume18
Issue number7
DOIs
StatePublished - Jul 2017

Keywords

  • ATP synthase
  • calcium
  • channels
  • mitochondria
  • permeability transition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint

Dive into the research topics of 'Ca<sup>2+</sup> binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition'. Together they form a unique fingerprint.

Cite this