Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Beta-adrenergic receptor signaling regulates ER-mitochondria contacts

View ORCID ProfileYoungshin Lim, Il-Taeg Cho, Helmut G. Rennke, View ORCID ProfileGinam Cho
doi: https://doi.org/10.1101/2020.05.11.088815
Youngshin Lim
aDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Youngshin Lim
Il-Taeg Cho
aDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
bDepartment of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Helmut G. Rennke
aDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ginam Cho
aDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ginam Cho
  • For correspondence: gpcho@bwh.harvard.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that these agonists promote physical and functional interactions between the two organelles. Inhibiting EPAC (exchange protein directly activated by cAMP) or CDC42 (cell division cycle 42) activity blocked the β-AR signaling-induced ER-Mito contacts. Furthermore, our data implicate that actin filament assembly, likely triggered by CDC42 upon β-AR activation, is a driving force for ER-Mito interaction. Together our study identifies β-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.

Significance Statement Here we identify β-adrenergic receptor (β-AR) signaling as an essential pathway controlling ER-Mito contacts. Uncovering the potential downstream effectors, our results provide novel insights into how GPCRs can modulate the ER-Mito coupling to elicit appropriate cellular responses. Our successful compound screen demonstrates that the split-Rluc assay is an optimal, valid assay for screening, as it readily adapts to a high throughput detection in live cells without artifacts associated with fixation or complications related to image analysis. Furthermore, our findings propose a novel mechanism of action for β-AR agonists, shown beneficial in Parkinson’s disease (PD), and suggests β-AR signaling as a potential druggable target for multiple conditions associated with ER-Mito contact dysregulation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Competing Interest Statement: The authors declare no competing interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Classification: Biological Sciences and Cell Biology

  • New data added in Fig 2, 3 and 4 as well as in Supplemental figures.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted March 25, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Beta-adrenergic receptor signaling regulates ER-mitochondria contacts
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Beta-adrenergic receptor signaling regulates ER-mitochondria contacts
Youngshin Lim, Il-Taeg Cho, Helmut G. Rennke, Ginam Cho
bioRxiv 2020.05.11.088815; doi: https://doi.org/10.1101/2020.05.11.088815
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Beta-adrenergic receptor signaling regulates ER-mitochondria contacts
Youngshin Lim, Il-Taeg Cho, Helmut G. Rennke, Ginam Cho
bioRxiv 2020.05.11.088815; doi: https://doi.org/10.1101/2020.05.11.088815

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cell Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3691)
  • Biochemistry (7800)
  • Bioengineering (5678)
  • Bioinformatics (21295)
  • Biophysics (10582)
  • Cancer Biology (8179)
  • Cell Biology (11946)
  • Clinical Trials (138)
  • Developmental Biology (6764)
  • Ecology (10401)
  • Epidemiology (2065)
  • Evolutionary Biology (13874)
  • Genetics (9709)
  • Genomics (13074)
  • Immunology (8150)
  • Microbiology (20020)
  • Molecular Biology (7859)
  • Neuroscience (43070)
  • Paleontology (321)
  • Pathology (1279)
  • Pharmacology and Toxicology (2260)
  • Physiology (3353)
  • Plant Biology (7232)
  • Scientific Communication and Education (1313)
  • Synthetic Biology (2008)
  • Systems Biology (5539)
  • Zoology (1128)