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Article Dans Une Revue Cell Death and Differentiation Année : 2016

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3beta during reperfusion injury

L. Gomez
P. A. Thiebaut
  • Fonction : Auteur
M. Paillard
S. Ducreux
M. Abrial
  • Fonction : Auteur
C. Crola da Silva
A. Durand
  • Fonction : Auteur
M. R. Alam
  • Fonction : Auteur
F. van Coppenolle
S. S. Sheu
  • Fonction : Auteur

Résumé

Glycogen synthase kinase-3beta (GSK3beta) is a multifunctional kinase whose inhibition is known to limit myocardial ischemia-reperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3beta might have a role in the Ca(2+) transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3beta protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3beta specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP3Rs) Ca(2+) channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3beta decreased protein interaction of IP3R with the Ca(2+) channeling complex, impaired SR/ER Ca(2+) release and reduced the histamine-stimulated Ca(2+) exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3beta activity and IP3R phosphorylation, which leads to enhanced transfer of Ca(2+) from SR/ER to mitochondria. Inhibition of GSK3beta at reperfusion reduced both IP3R phosphorylation and SR/ER Ca(2+) release, which consequently diminished both cytosolic and mitochondrial Ca(2+) concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3beta at reperfusion diminishes Ca(2+) leak from IP3R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca(2+) overload and subsequent cell death.

Dates et versions

hal-01850428 , version 1 (27-07-2018)

Identifiants

Citer

L. Gomez, P. A. Thiebaut, M. Paillard, S. Ducreux, M. Abrial, et al.. The SR/ER-mitochondria calcium crosstalk is regulated by GSK3beta during reperfusion injury. Cell Death and Differentiation, 2016, 23 (2), pp.313-22. ⟨10.1038/cdd.2015.101⟩. ⟨hal-01850428⟩
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