Ca(2+) binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition.

TitleCa(2+) binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition.
Publication TypeJournal Article
Year of Publication2017
AuthorsGiorgio, V, Burchell, V, Schiavone, M, Bassot, C, Minervini, G, Petronilli, V, Argenton, F, Forte, M, Tosatto, S, Lippe, G, Bernardi, P
JournalEMBO Rep
Volume18
Issue7
Pagination1065-1076
Date Published2017 Jul
ISSN1469-3178
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.

DOI10.15252/embr.201643354
Alternate JournalEMBO Rep.
Citation Key10.15252/embr.201643354
PubMed ID28507163
PubMed Central IDPMC5494526