Acute Induction of Translocon-Mediated Ca(2+) Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury

During myocardial infarction, dysregulation of Ca(2+) homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca(2+) leak channels are thought to be key regulators of the reticular Ca(2+) homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca(2+) leak channel, the translocon, also known as translocation channel, could be a relevant target against ischemia/reperfusion-mediated heart injury. To achieve this objective, we first used an intramyocardial adenoviral strategy to express biosensors in order to assess Ca(2+) variations in freshly isolated adult mouse cardiomyocytes to show that translocon is a functional reticular Ca(2+) leak channel. Interestingly, translocon activation by puromycin mobilized a ryanodine receptor (RyR)-independent reticular Ca(2+) pool and did not affect the excitation–concentration coupling. Second, puromycin pretreatment decreased mitochondrial Ca(2+) content and slowed down the mitochondrial permeability transition pore (mPTP) opening and the rate of cytosolic Ca(2+) increase during hypoxia. Finally, this translocon pre-activation also protected cardiomyocytes after in vitro hypoxia reoxygenation and reduced infarct size in mice submitted to in vivo ischemia-reperfusion. Altogether, our report emphasizes the role of translocon in cardioprotection and highlights a new paradigm in cardioprotection by functionally uncoupling the RyR-dependent Ca(2+) stores and translocon-dependent Ca(2+) stores.