From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, People's Republic of China (Y.C., C.X., J.Y., X.Z., S.J., X.Q., C.Z., R.L., L.W., Y.L., L.L., M.Z.).
Medical and Health Analysis Center, Peking University, Beijing, People's Republic of China (Q.H.).
Circ Res. 2019 Sep 27;125(8):728-743. doi: 10.1161/CIRCRESAHA.119.315432. Epub 2019 Aug 28.
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. To determine the molecular mechanism underlying the robust inter-mitochondrial communication and its pathophysiological relevance in the heart. 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. 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.
心肌细胞中的约束线粒体通过线粒体亲吻或纳米管相互沟通，形成一个动态连续的网络，以共享内容和传递信号。然而，心脏细胞间线粒体通讯的分子机制尚不清楚。为了确定强大的心脏细胞间线粒体通讯的分子机制及其在心脏疾病中的病理生理相关性。通过线粒体靶向表达光激活绿色荧光蛋白，我们揭示了大多数连接通讯线粒体对的线粒体纳米管与微管有关。Miro2（线粒体 Rho GTPase）是一种通常介导细胞内线粒体运输的外线粒体膜蛋白，与成年心肌细胞中的线粒体纳米管一起沿着微管排列。腺病毒介导的 Miro2 在心肌细胞中的表达通过增加相邻线粒体对之间的线粒体纳米通道和线粒体亲吻来加速细胞间线粒体通讯。在主动脉缩窄诱导的肥厚小鼠心脏中，Miro2 蛋白减少，伴随细胞间线粒体通讯减少。Miro2 转基因小鼠在主动脉缩窄后表现出心脏功能改善、线粒体纳米管形成和细胞间线粒体通讯增加以及线粒体功能改善。Parkin 是一种 E3 泛素连接酶，在主动脉缩窄小鼠心脏和苯肾上腺素刺激诱导的肥厚心肌细胞中增加。蛋白酶体抑制剂阻断苯肾上腺素诱导的 Miro2 减少，Parkin 过表达导致 Miro2 减少。线粒体 Miro2 表达水平调节成年心肌细胞中线粒体沿微管的细胞间通讯，Parkin 介导的泛素化导致 Miro2 降解，导致肥厚性心脏病期间细胞间线粒体通讯受损和心脏功能障碍。
