Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2024-10-07 Epub Date: 2024-08-12 DOI:10.1083/jcb.202304031
Shue Chen, Yang Sun, Yuling Qin, Lan Yang, Zhenhua Hao, Zhihao Xu, Mikael Björklund, Wei Liu, Zhi Hong
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Abstract

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.

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REEP5-MFN1/2 的动态相互作用使线粒体能够在管状 ER 上搭便车。
线粒体的功能可以通过与内质网(ER)的膜接触点来调节。这些线粒体-ER接触位点(MERCs)在功能上是异质的,由不同的系链维持。在这里,我们发现ER小管塑形蛋白REEP5与Mitofusins 1/2相互作用,通过一种新的运输机制--线粒体在微管上与管状ER "搭便车"--介导线粒体在整个细胞质中的分布。耗尽 REEP5 会导致线粒体的系链减少和核周定位增加。相反,增加 REEP5 的表达则有利于线粒体在整个细胞质中的分布。雷帕霉素诱导的 REEP5-MFN1/2 不可逆相互作用导致线粒体过度融合,这意味着线粒体从系链中动态释放是线粒体正常分布和动态变化的必要条件。从功能上讲,通过强迫二聚化或沉默 REEP5 来破坏 MFN2-REEP5相互作用的动态,可调节线粒体活性氧(ROS)的产生。总之,我们的研究结果表明,REEP5-MFN1/2的动态相互作用通过 "搭便车 "介导线粒体网络的胞浆分布和连接,这一过程调节线粒体ROS,而ROS对多种生理功能至关重要。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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