Grpel2 alleviates myocardial ischemia/reperfusion injury by inhibiting MCU-mediated mitochondrial calcium overload.

Mitochondrial calcium ([Ca2+]m) overload is considered a major trigger of cardiomyocyte death during myocardial ischemia/reperfusion (I/R) injury. Grpel2 is located in mitochondria and facilitates the mtHSP70 protein folding cycle in oxidative stress. However, Grpel2 expression during I/R injury and its impact on I/R injury remain poorly understood. This study explored the role of Grpel2 in I/R injury and its underlying mechanism. Mice were intramyocardially injected with recombinant adenovirus vectors to knockdown cardiac Grpel2 expression, and a myocardial I/R model was established. We confirmed that cardiac Grpel2 is upregulated during I/R injury. Cardiac-specific Grpel2 knockdown exacerbates mitochondrial fission, cardiomyocyte death and cardiac contractile dysfunction induced by I/R injury. Moreover, our study revealed that Grpel2 knockdown increased both MCU expression and [Ca2+]m content. Excessive mitochondrial fission and apoptosis were rescued by Ru360, an inhibitor of MCU opening. In summary, our findings suggest that Grpel2 alleviates myocardial ischemia/reperfusion injury by inhibiting MCU-mediated mitochondrial calcium overload and provide new insights into the mechanism of MCU-mediated [Ca2+]m homeostasis during I/R injury.