ZFIN ID: ZDB-PUB-170517-8
Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition.
Giorgio, V., Burchell, V., Schiavone, M., Bassot, C., Minervini, G., Petronilli, V., Argenton, F., Forte, M., Tosatto, S., Lippe, G., Bernardi, P.
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.
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.
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