Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver

Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are essential for lipid metabolism. In this study, liver-specific Drp1 knockout (Drp1LiKO) mice were utilized to investigate the impact of disrupted organelle interactions. Analysis revealed increased interactions between mitochondria and LDs, as well as among ER, mitochondria, and LDs in Drp1LiKO mice. As a result, impaired fatty acid metabolism was observed, leading to liver inflammation. In vitro studies using primary hepatocytes from Drp1LiKO mice further confirmed disrupted lipid metabolism and increased inflammation. These findings underscore the significance of Drp1 in maintaining organelle interactions for proper lipid metabolism and liver health. Targeting Drp1-mediated interactions may present a promising approach for the treatment of liver diseases associated with lipid metabolism dysregulation. We have reported that disruption of mitochondrial fission by deletion of Drp1 leads to an alteration in expression of the genes involved in the immune system in the liver and significant elevation of pro-inflammatory cytokines was detected in Drp1 knockout cells. To fully reveal the gene expression altered by Drp1 deletion, we conducted an independent microarray analysis with primary hepatocyte harvested 24 hours after seeding.