The SR/ER-mitochondria calcium crosstalk is regulated by GSK3ß during reperfusion injury.
Cell Death Differ
; 23(2): 313-22, 2016 Feb.
Article
en En
| MEDLINE
| ID: mdl-26206086
Glycogen synthase kinase-3ß (GSK3ß) 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 GSK3ß might have a role in the Ca(2+) transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3ß protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3ß 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 GSK3ß 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 GSK3ß activity and IP3R phosphorylation, which leads to enhanced transfer of Ca(2+) from SR/ER to mitochondria. Inhibition of GSK3ß 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 GSK3ß 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Retículo Sarcoplasmático
/
Daño por Reperfusión Miocárdica
/
Señalización del Calcio
/
Glucógeno Sintasa Quinasa 3
/
Mitocondrias Cardíacas
Límite:
Animals
Idioma:
En
Revista:
Cell Death Differ
Año:
2016
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Reino Unido