Targeting DRP1Ser637 Phosphorylation Alleviates Acidic Bile Salt-Induced NF-κB Activation via Mitochondrial Protection.

BACKGROUND AND AIMS: The role of mitochondrial dynamics in gastroesophageal reflux disease (GERD) remains unclear. We investigated how bile acid-induced mitochondrial dysfunction triggers mucosal inflammation and explored therapeutic targets.

METHODS

Esophageal mucosal biopsies from 12 GERD patients and 12 controls underwent RNA-seq. Human esophageal epithelial cells (HEEC) were treated with acidic bile salts (ABS, pH 5.5). Mitochondrial morphology (TOMM20 immunofluorescence), function (TMRM/MitoSOX staining), and DRP1 post-translational modifications (non-reducing Western blot) were analyzed. DRP1 knockdown (shRNA) and pharmacological inhibition (H-89) were used to validate mechanisms.

RESULTS

RNA-seq revealed enrichment of mitochondrial fission and NF-κB pathways in GERD patients. ABS exposure in HEEC increased DRP1 Ser637 phosphorylation, inducing mitochondrial fragmentation, membrane potential loss, and mtROS overproduction. Paradoxically, DRP1 knockdown exacerbated mitochondrial damage and amplified NF-κB activation. H-89 suppressed DRP1 Ser637 phosphorylation, restored mitochondrial function, and attenuated IL-6/IL-8 secretion. This effect was abolished in DRP1-knockdown cells.

CONCLUSIONS

ABS-induced DRP1 Ser637 phosphorylation drives mitochondrial fragmentation and mtROS-dependent NF-κB activation in GERD. DRP1-mediated fission paradoxically limits mucosal damage by enabling quality control. Targeting DRP1 phosphorylation may offer a novel therapeutic strategy to break the mitochondrial-inflammation vicious cycle in GERD.