Acute Induction of Translocon-Mediated Ca2+ Leak Protects Cardiomyocytes Against Ischemia/Reperfusion Injury

Cells

Yves Gouriou¹  Alexandre Paccalet¹  Claire Crola Da Silva¹  Ribal Al-Mawla¹  Mallory Ducrozet¹  Michel Ovize¹  Lucille Païta¹  Bruno Pillot¹  Camille Villedieu¹  Nolwenn Tessier¹  Fabien Van Coppenolle¹  Zeina Harhous¹  Gabriel Bidaux¹  Sylvie Ducreux¹ 

[1] Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69500 Bron, France;

关键词: Ca²⁺ leak channel;    translocon;    reticulum;    cardioprotection;    ischemia-reperfusion;   

DOI  :  10.3390/cells9051319

来源: DOAJ

【 摘 要 】

During myocardial infarction, dysregulation of Ca²⁺ homeostasis between the reticulum, mitochondria, and cytosol occurs in cardiomyocytes and leads to cell death. Ca²⁺ leak channels are thought to be key regulators of the reticular Ca²⁺ homeostasis and cell survival. The present study aimed to determine whether a particular reticular Ca²⁺ 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 Ca²⁺ variations in freshly isolated adult mouse cardiomyocytes to show that translocon is a functional reticular Ca²⁺ leak channel. Interestingly, translocon activation by puromycin mobilized a ryanodine receptor (RyR)-independent reticular Ca²⁺ pool and did not affect the excitation–concentration coupling. Second, puromycin pretreatment decreased mitochondrial Ca²⁺ content and slowed down the mitochondrial permeability transition pore (mPTP) opening and the rate of cytosolic Ca²⁺ 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 Ca²⁺ stores and translocon-dependent Ca²⁺ stores.

【 授权许可】

Unknown