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Updated: Jun 17, 2025
Author Spotlight: Regulation and Dysregulation of ER-Mitochondria Contacts — Implications for Neurodegenerative Disease Pathogenesis
Published on: October 11, 2024
Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER
Shue Chen1,2,3, Yang Sun1,2, Yuling Qin1,2
1Department of Neurology, the Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang University, Hangzhou, China.
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.
Insights
Mitochondria distribution is regulated by REEP5 protein interacting with Mitofusins 1/2, enabling "hitchhiking" on ER tubules along microtubules. This dynamic interaction controls mitochondrial ROS production, crucial for cell function.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- ER-Mitochondria Interactions
Background:
- Mitochondria-ER contact sites (MERCs) regulate mitochondrial functions.
- MERCs are heterogeneous and maintained by various tethering proteins.
- The role of specific ER proteins in MERC dynamics and mitochondrial distribution is not fully understood.
Purpose of the Study:
- To investigate the role of REEP5 in mediating mitochondrial distribution and dynamics.
- To elucidate the mechanism of mitochondrial transport via ER tubules.
- To determine the impact of REEP5-mediated interactions on mitochondrial reactive oxygen species (ROS) production.
Main Methods:
- Co-immunoprecipitation to assess protein interactions (REEP5-Mitofusins).
- Cellular imaging to observe mitochondrial distribution and morphology.
- RNA interference (RNAi) to deplete REEP5 expression.
- Rapamycin-induced dimerization to study forced interactions.
Main Results:
- REEP5 interacts with Mitofusins 1/2 (MFN1/2) to mediate mitochondrial "hitchhiking" with ER tubules on microtubules.
- REEP5 depletion causes reduced mitochondrial tethering and perinuclear clustering.
- Increased REEP5 expression promotes broader cytosolic mitochondrial distribution.
- Disruption of REEP5-MFN interaction dynamics affects mitochondrial ROS production.
Conclusions:
- Dynamic REEP5-MFN1/2 interaction is a novel mechanism for mitochondrial cytosolic distribution and network connectivity.
- This "hitchhiking" process regulates mitochondrial ROS, impacting cellular physiology.
- Understanding these dynamics offers insights into mitochondrial health and disease.
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