MCU Up-regulation contributes to myocardial ischemia-reperfusion Injury through calpain/OPA-1-mediated mitochondrial fusion/mitophagy Inhibition
MCU Up-regulation contributes to myocardial ischemia-reperfusion Injury through calpain/OPA-1-mediated mitochondrial fusion/mitophagy Inhibition
复制标题
MCU 上调通过钙蛋白酶/OPA-1 介导的线粒体融合/线粒体自噬抑制导致心肌缺血再灌注损伤
DOI：
10.1111/jcmm.14662
复制
发表时间：
2019-09-09
影响因子：
2.7
通讯作者：
Yu, Min
中科院分区：
文献类型：
--
作者：
Guan, Lichun;Che, Zhimei;Yu, Min
线粒体动力学紊乱参与了心肌缺血/再灌注损伤。建立小鼠心肌I/R模型和小鼠心肌细胞缺氧/复氧模型，探讨线粒体钙单转运体(MCU)在心肌I/R损伤中的作用及其信号转导途径。MCU在I/R过程中表达增加，与心肌损伤、线粒体分裂增强、线粒体融合抑制和有丝分裂有关。Ru360抑制MCU功能可减少心肌梗死面积，减少心肌细胞凋亡，减轻线粒体分裂，恢复线粒体融合和有丝分裂。而给予精胺可增强MCU功能，加重上述心肌细胞损伤和线粒体动态平衡。此外，MCU的上调促进了Calain-1/2的表达和激活，下调了视神经萎缩1型(OPA1)的表达。同时，在转基因小鼠(过表达钙蛋白酶的内源性抑制物calastatin)I/R模型和OPA1基因敲除培养的细胞中。在高表达钙蛋白酶的内源性抑制剂calastatin的转基因小鼠的I/R模型中，以及在siOPA1转基因的H/R模型中，抑制calain可以促进线粒体的融合和有丝分裂，并通过OPA1抑制线粒体的过度分裂和凋亡。因此，我们得出结论，在I/R过程中，MCU上调诱导Calain激活，进而下调OPA1，从而导致线粒体动态失衡。
Mitochondrial dynamic disorder is involved in myocardial ischemia/reperfusion (I/R) injury. To explore the effect of mitochondrial calcium uniporter (MCU) on mitochondrial dynamic imbalance under I/R and its related signal pathways, a mouse myocardial I/R model and hypoxia/reoxygenation model of mouse cardiomyocytes were established. The expression of MCU during I/R increased and related to myocardial injury, enhancement of mitochondrial fission, inhibition of mitochondrial fusion and mitophagy. Suppressing MCU functions by Ru360 during I/R could reduce myocardial infarction area and cardiomyocyte apoptosis, alleviate mitochondrial fission and restore mitochondrial fusion and mitophagy. However, spermine administration, which could enhance MCU function, deteriorated the above-mentioned myocardial cell injury and mitochondrial dynamic imbalanced. In addition, up-regulation of MCU promoted the expression and activation of calpain-1/2 and down-regulated the expression of Optic atrophy type 1 (OPA1). Meantime, in transgenic mice (overexpression calpastatin, the endogenous inhibitor of calpain) I/R model and OPA1 knock-down cultured cell. In I/R models of transgenic mice over-expressing calpastatin, which is the endogenous inhibitor of calpain, and in H/R models with siOPA1 transfection, inhibition of calpains could enhance mitochondrial fusion and mitophagy, and inhibit excessive mitochondrion fission and apoptosis through OPA1. Therefore, we conclude that during I/R, MCU up-regulation induces calpain activation, which down-regulates OPA1, consequently leading to mitochondrial dynamic imbalance.