Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.

中文翻译：

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REEP5-MFN1/2 的动态相互作用使线粒体能够搭上管状 ER 的便车。


线粒体功能可以通过膜与内质网（ER）的接触位点进行调节。这些线粒体-内质网接触位点（MERC）在功能上是异质的，并由不同的系链维持。在这里，我们发现 REEP5（一种 ER 小管塑造蛋白）与 Mitofusins 1/2 相互作用，通过一种新的转运机制（线粒体与微管上的管状 ER 搭便车）介导线粒体在整个细胞质中的分布。 REEP5 耗尽导致线粒体束缚减少和核周定位增加。相反，增加 REEP5 表达有利于线粒体在整个细胞质中的分布。雷帕霉素诱导的不可逆 REEP5-MFN1/2 相互作用导致线粒体过度融合，这意味着线粒体从束缚中动态释放对于正常的线粒体分布和动力学是必要的。从功能上讲，通过强制二聚化或沉默 REEP5 来破坏 MFN2-REEP5 相互作用动力学可调节线粒体活性氧 (ROS) 的产生。总体而言，我们的结果表明，动态 REEP5-MFN1/2 相互作用通过“搭便车”介导线粒体网络的胞质分布和连接性，并且该过程调节线粒体 ROS，这对于多种生理功能至关重要。