DRP1 tethered trafficking vesicles at ER. (A) Representative HepG2 cell DRP1 immunogold electron microscopy. Arrows, ER exit sites DRP1 (black dots); arrow heads, cytosolic vesicles DRP1; color box zoomed-in insets, DRP1 tethering trafficking vesicles at ER; scale bars, 100 nm. (B) Confocal analysis of human DRP1 protein tethering unilaminar vesicles; white arrows indicate examples of tethered vesicles; n = 3 experimental replicates. Representative confocal Z-stack image of GFP-tagged DRP1 tethering vesicles, width 97.70 μm, height 97.7 μm, and depth 38.40 μm. Image also included as Supplementary material online, Video 1. (C) Working model. DRP1 inhibition suppresses remodeling of select ER microdomains and select protein trafficking out of ER, including PCSK9, leading to increased PCSK9 degradation by trafficking from ER to proteasomes via ER chaperone GRP94 to maintain ER homeostasis. Additionally, DRP1 inhibition transcriptionally suppresses PCSK9 mRNA in specific conditions via SREBP regulation, such as in HepG2 cells by reducing SREBP-1c.