Drp1-mediated mitochondrial fission exacerbates inflammatory responses in intestinal epithelial cells: A potential...

Inflammatory bowel disease (IBD) is a chronic inflammatory condition characterized by immune-mediated damage to the intestinal barrier. Mitochondrial fission, a crucial regulator of cellular homeostasis, has been increasingly implicated in IBD pathogenesis, although its precise role remains to be fully elucidated. This study investigated how mitochondrial fission contributes to intestinal inflammation and whether its inhibition can mitigate inflammatory responses. Human colorectal adenocarcinoma cells (HT-29) were treated with lipopolysaccharide and TNF-α (tumor necrosis factor-alpha) to induce inflammation. To assess the role of mitochondrial fission, we used pharmacological inhibition (Mdivi-1 and P110) as well as genetic suppression (Drp1 knockdown via siDrp1). Mitochondrial function was evaluated via oxygen consumption rate, assessments of ATP production, and analyses of mitochondrial membrane potential (ΔΨm). Inflammatory responses were assessed using Western blotting and qRT-PCR. Intestinal barrier integrity was evaluated by measuring trans-epithelial electrical resistance (TEER). Lipopolysaccharide stimulation promoted Drp1 translocation to mitochondria, enhancing mitochondrial fission and dysfunction. Drp1 inhibition significantly reduced pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6), suppressed NF-κB and MAPK activation, and restored mitochondrial function by reducing mitochondrial reactive oxygen species. Additionally, Drp1 inhibition downregulated inducible nitric oxide synthase and cyclooxygenase-2, key inflammatory enzymes, and effectively preserved epithelial barrier integrity, as demonstrated by significantly improved TEER values. These findings provide evidence that excessive mitochondrial fission contributes to intestinal inflammation and barrier dysfunction, and that targeting Drp1 can restore mitochondrial and epithelial homeostasis. By demonstrating that Drp1 inhibition suppresses inflammatory signaling, preserves mitochondrial integrity, and maintains epithelial barrier function, this study highlights mitochondrial fission as a potential therapeutic target for IBD treatment. Further validation using in vivo models and patient-derived tissues is warranted to confirm the clinical applicability of these findings.