Miro2 Regulates Inter-Mitochondrial Communication in the Heart and Protects Against TAC-Induced Cardiac Dysfunction
Miro2 Regulates Inter-Mitochondrial Communication in the Heart and Protects Against TAC-Induced Cardiac Dysfunction
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Miro2 调节心脏线粒体间通讯并预防 TAC 引起的心脏功能障碍
DOI：
10.1161/circresaha.119.315432
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发表时间：
2019-09-27
影响因子：
20.1
通讯作者：
Zheng, Ming
中科院分区：
文献类型：
--
作者：
Cao, Yangpo;Xu, Chunling;Zheng, Ming
原理：心肌细胞内受限的线粒体通过线粒体接吻或纳米隧道相互通信，形成一个动态连续的网络来共享内容和传递信号。然而，心脏线粒体间通讯的分子机制尚不清楚。目的：探讨心脏线粒体间通讯的分子机制及其病理生理意义。方法与结果：通过线粒体靶向表达光激活绿色荧光蛋白，我们发现大多数线粒体纳米管与微管相关。Miro2（线粒体Rho GTPase），线粒体外膜蛋白，通常介导线粒体在细胞内的运输，伴随着线粒体纳米管沿着微管在成人心肌细胞。腺病毒介导的心肌细胞中Miro2的表达通过增加线粒体纳米隧道和相邻线粒体对之间的线粒体接吻来加速线粒体间的通讯。在主动脉缩窄引起的肥厚小鼠心脏中，Miro2蛋白下降，线粒体间通讯减少。Miro2转基因小鼠在主动脉横缩后心功能改善，线粒体纳米管形成和线粒体间通讯增加，线粒体功能改善。E3泛素连接酶Parkin在横断主动脉收缩小鼠心脏和苯肾上腺素刺激诱导的肥厚心肌细胞中升高。蛋白酶体的抑制阻断了苯肾上腺素诱导的Miro2的降低，Parkin过表达导致了Miro2的降低。结论：线粒体Miro2表达水平调节成体心肌细胞沿微管的线粒体间通讯，通过帕金森介导的泛素化降解Miro2有助于肥厚性心脏病期间线粒体间通讯受损和心功能障碍。可视化概述：本文提供了一个在线可视化概述。
Rationale: The constrained mitochondria in cardiomyocytes communicate with each other, through mitochondrial kissing or nanotunneling, forming a dynamically continuous network to share content and transfer signals. However, the molecular mechanism of cardiac inter-mitochondrial communication is unclear. Objective: To determine the molecular mechanism underlying the robust inter-mitochondrial communication and its pathophysiological relevance in the heart. Methods and Results: By mitochondria-targeted expressing the photoactivatable green fluorescent protein, we revealed that most mitochondrial nanotubes bridge communicating mitochondrial pairs were associated with microtubules. Miro2 (mitochondrial Rho GTPase), the outer mitochondrial membrane protein which usually mediates mitochondrial transport within cells, accompanied with mitochondrial nanotubes along microtubules in adult cardiomyocytes. Adenovirus mediated expression of Miro2 in cardiomyocytes accelerated inter-mitochondrial communication through increasing mitochondrial nanotunneling and mitochondrial kissing between adjacent mitochondrial pairs. In transverse aortic constriction-induced hypertrophic mouse hearts Miro2 protein was declined, accompanied with decreased inter-mitochondrial communication. Miro2 transgenic mice showed ameliorated cardiac function, increased mitochondrial nanotube formation and inter-mitochondrial communication, and improved mitochondrial function after transverse aortic constriction. E3 ubiquitin ligase Parkin was increased in transverse aortic constriction mouse hearts and phenylephrine stimulation-induced hypertrophic cardiomyocytes. Inhibition of proteasome blocked phenylephrine-induced decrease of Miro2, and Parkin overexpression led to the decrease of Miro2. Conclusions: Mitochondrial Miro2 expression levels regulate inter-mitochondrial communication along microtubules in adult cardiomyocytes, and degradation of Miro2 through Parkin-mediated ubiquitination contributes to impaired inter-mitochondrial communication and cardiac dysfunction during hypertrophic heart diseases.Visual Overview: An online visual overview is available for this article.