PT - JOURNAL ARTICLE AU - Lim, Youngshin AU - Cho, Il-Taeg AU - Rennke, Helmut G. AU - Cho, Ginam TI - Beta-adrenergic receptor signaling regulates ER-mitochondria contacts AID - 10.1101/2020.05.11.088815 DP - 2021 Jan 01 TA - bioRxiv PG - 2020.05.11.088815 4099 - http://biorxiv.org/content/early/2021/03/25/2020.05.11.088815.short 4100 - http://biorxiv.org/content/early/2021/03/25/2020.05.11.088815.full AB - 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 StatementThe authors have declared no competing interest.