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

• Published in: Cells (Basel, Switzerland) Switzerland), 2020-05, Vol.9 (5)
• Main Authors: Al-Mawla, Ribal, Ducrozet, Mallory, Tessier, Nolwenn, Païta, Lucille, Pillot, Bruno, Gouriou, Yves, Villedieu, Camille, Harhous, Zeina, Paccalet, Alexandre, Crola Da Silva, Claire, Ovize, Michel, Bidaux, Gabriel, Ducreux, Sylvie, Van Coppenolle, Fabien
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cardiotonic Agents - metabolism; Excitation Contraction Coupling; Male; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Permeability Transition Pore - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Puromycin - pharmacology; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Ryanodine Receptor Calcium Release Channel - metabolism; SEC Translocation Channels - metabolism
• ISSN: 2073-4409

During myocardial infarction, dysregulation of Ca homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca leak channels are thought to be key regulators of the reticular Ca homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca 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 variations in freshly isolated adult mouse cardiomyocytes to show that translocon is a functional reticular Ca leak channel. Interestingly, translocon activation by puromycin mobilized a ryanodine receptor (RyR)-independent reticular Ca pool and did not affect the excitation-concentration coupling. Second, puromycin pretreatment decreased mitochondrial Ca content and slowed down the mitochondrial permeability transition pore (mPTP) opening and the rate of cytosolic Ca 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 stores and translocon-dependent Ca stores.