PUBLICATION
Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition.
- Authors
- Giorgio, V., Burchell, V., Schiavone, M., Bassot, C., Minervini, G., Petronilli, V., Argenton, F., Forte, M., Tosatto, S., Lippe, G., Bernardi, P.
- ID
- ZDB-PUB-170517-8
- Date
- 2017
- Source
- EMBO reports 18(7): 1065-1076 (Journal)
- Registered Authors
- Argenton, Francesco, Schiavone, Marco
- Keywords
- ATP synthase, calcium, channels, mitochondria, permeability transition
- MeSH Terms
-
- Animals
- Biological Transport
- Calcium/metabolism*
- Catalytic Domain
- Cell Death
- Cell Differentiation
- Embryo, Nonmammalian/cytology
- HeLa Cells
- Humans
- Hydrolysis
- Mitochondria/metabolism
- Mitochondrial Membrane Transport Proteins/chemistry
- Mitochondrial Membrane Transport Proteins/metabolism*
- Mitochondrial Membranes/metabolism*
- Mitochondrial Proton-Translocating ATPases/chemistry
- Mitochondrial Proton-Translocating ATPases/metabolism*
- Permeability
- Protein Binding
- Protein Conformation
- Zebrafish/embryology
- PubMed
- 28507163 Full text @ EMBO Rep.
Citation
Giorgio, V., Burchell, V., Schiavone, M., Bassot, C., Minervini, G., Petronilli, V., Argenton, F., Forte, M., Tosatto, S., Lippe, G., Bernardi, P. (2017) Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition.. EMBO reports. 18(7):1065-1076.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping