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 language | English (US) |
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Pages (from-to) | 1065-1076 |
Number of pages | 12 |
Journal | EMBO Reports |
Volume | 18 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2017 |
Keywords
- ATP synthase
- calcium
- channels
- mitochondria
- permeability transition
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Genetics