A Novel Mitochondrial Fission Inhibitor Ameliorates DSS and DNBS Induced Murine Colitis

Abstract

SignificanceInflammatory bowel disease (IBD) encompasses a group of disorders that involve an exaggerated immune response to intestinal microbes. Maintenance of intestinal epithelial barrier function is highly dependent on normal mitochondrial networks. When the barrier is compromised, excessive pathological fission ensues via the enzyme dynamin related protein‐1 (DRP1) and its interaction with the receptor fission protein‐1 (Fis1), creating fragmented networks of mitochondria. Fragmented mitochondrial networks have impaired respiratory capacity, generate elevated reactive oxygen species and exacerbate inflammationObjectiveTo determine whether a novel peptide, P110, can mitigate dextran sodium sulfate (DSS) and dinitrobenzene sulfonic acid (DNBS) induced colitis by inhibiting DRP1 and Fis1 mediated fission in murine models.DesignHypothesising that elevated mitochondrial fission occurs in DSS and DNBS colitis, male Balb/c mice were split into control (n=15), P110 (3 mg/kg/d, intraperitoneally)(n=8), DSS (5% (w/v), 5 days + 3 days water)(n=16) and DSS+P110 (n=16). For the DNBS protocol, male Balb/c mice were divided into control (n=8), DNBS (3 mg/kg/d, intraperitoneally)(n=11) and DNBS+P110 (3 mg/kg/d, intraperitoneally)(n=8). Experimental measures included: body mass, colon length, macroscopic disease score, cross‐sectional histopathology and colonic motility.ResultsUpon necropsy DSS and DNBS treated mice displayed the characteristic signs of colitis associated with these models. Disease was substantially less in both DSS+P110 and DNBS+P110 treated mice as gauged by: (i) percent weight loss (ii) macroscopic disease score and (iii) colon shortening (p<0.05). Functional improvements in colonic motility were seen in P110 treated mice when compared to DSS alone (p<0.05). Analysis of histopathology on H&E stained sections of mid‐colon revealed significant improvement in DNBS mice with P110 (p<0.05). P110 was also found to improve survival rate of mice, compared to DNBS alone.ConclusionsSystemic administration of a selective inhibitor of mitochondrial fission (P110) reduced the severity of disease in two different, commonly used murine models of colitis. Future studies are required to define the mechanism of P110's action in terms of the target cell in IBD (e.g. epithelium, nerve, macrophage). We conclude that inhibition of DRP1 and Fis1 interaction provides a novel approach to mitigating gut barrier deterioration in IBDSupport or Funding InformationCrohn's and Colitis Canada. The authors wish to thank Daria Mochly‐Rosen for donating P110.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Expression of Oxidative Phosphorylation Complexes and Mitochondrial Mass in Pediatric and Adult Inflammatory Bowel Disease

“…MFN1, MFN2, OPA1, and p-DRP1 levels increased in a model of DSS-induced colitis [ 60 , 61 ]. A mitochondrial fission inhibitor ameliorated DSS- and DNBS-induced murine colitis [ 62 ]. Whether a therapeutic intervention that shifts mitochondrial turnover to either fission or fusion would be beneficial remains to be elucidated.…”