Department of Cardiology, Xijing Hospital, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, China; Department of Cardiology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, 710038, China.
Department of Cardiology, Xijing Hospital, Air Force Medical University, 169 Changle West Road, Xi'an, 710032, China.
Biochem Biophys Res Commun. 2022 Jun 18;609:169-175. doi: 10.1016/j.bbrc.2022.04.014. Epub 2022 Apr 8.
Mitochondrial calcium ([Ca]) 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 [Ca] 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 [Ca] homeostasis during I/R injury.
线粒体钙 ([Ca]) 超载被认为是心肌缺血/再灌注 (I/R) 损伤期间心肌细胞死亡的主要触发因素。Grpel2 位于线粒体中，在氧化应激下促进 mtHSP70 蛋白折叠循环。然而，在 I/R 损伤期间 Grpel2 的表达及其对 I/R 损伤的影响仍知之甚少。本研究探讨了 Grpel2 在 I/R 损伤中的作用及其潜在机制。通过心肌内注射重组腺病毒载体来敲低心脏 Grpel2 的表达，建立心肌 I/R 模型。我们证实心脏 Grpel2 在 I/R 损伤期间上调。心脏特异性 Grpel2 敲低加重了 I/R 损伤诱导的线粒体分裂、心肌细胞死亡和心脏收缩功能障碍。此外，我们的研究表明 Grpel2 敲低增加了 MCU 的表达和 [Ca] 含量。MCU 开放抑制剂 Ru360 挽救了过度的线粒体分裂和细胞凋亡。总之，我们的研究结果表明 Grpel2 通过抑制 MCU 介导的线粒体钙超载减轻心肌缺血/再灌注损伤，为 MCU 介导的 I/R 损伤期间 [Ca] 稳态的机制提供了新的见解。
