Novel role of dynamin‐related‐protein 1 in dynamics of ER‐lipid droplets in adipose tissue

Abstract

Dynamin‐Related‐Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to β‐adrenergic stimulation. To further investigate the function of DRP1 on ER‐lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue‐specific DRP1 knockout model (Adipo‐Drp1flx/flx). We found that the LDs in adipose tissues of Adipo‐Drp1flx/flx mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro‐LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo‐Drp1flx/flx mice.

Insights on the role of l-lactate as a signaling molecule in skin aging

“…The dynamin related protein 1 (DRP1), which regulates mitochondria biogenesis and mitophagy, i.e., mitochondrial and peroxisome fission, regulates also endoplasmic reticulum-generated droplets in the adipose tissue, so correlating the correct lipid storage in adipocytes with the mitochondrial survival (Li et al 2020 ). Recent data on lung cancer cell models, reported that DRP1 promotes l -lactate utilization and suppresses oxidative stress from ROS (Hu et al 2020 ).…”

“…Recent data on lung cancer cell models, reported that DRP1 promotes l -lactate utilization and suppresses oxidative stress from ROS (Hu et al 2020 ). Targeting DRP1 allows to reducing the expression of heart shock proteins (hsp90) and increasing the ROS-mediated cleavage of hsp90, a mechanism that in turn will inhibit the MAPK and PI3K-mediated pathways, the ability of cell to use l -lactate and subsequently the ROS-mediated cell death (li et al 2020 ).…”

ncBAF, a chromatin remodeler, enhances PXR-mediated transcriptional activation in the human and mouse liver

“…The bands were quantified by using an Odyssey Infrared Imaging system (LI-COR Biosciences). The Cyp3a and CYP3A4 protein levels in C57BL/6J and hCYP3A-MAC/hPXR mice, respectively, were normalized to the KDEL protein level as described in a previous report (50).…”

The strange case of Drp1 in autophagy: Jekyll and Hyde?

“…[20] Of note, noncanonical functions of Drp1 have been postulated for the maintenance of mitochondrial respiration in adult rat cardiomyocytes, and in lipid droplet dynamics in mice adipose tissue. [21,22] The mammalian Drp1 locus is complex and codes for multiple Drp1 isoforms. The human Drp1 locus contains three different alternative splicing sites giving rise to nine different isoforms whose specific functions are mainly unknown.…”

“…[ 20 ] Of note, noncanonical functions of Drp1 have been postulated for the maintenance of mitochondrial respiration in adult rat cardiomyocytes, and in lipid droplet dynamics in mice adipose tissue. [ 21,22 ]…”