Investigating the Consequences of DRP1 and Fis1 Mediated Mitochondrial Fission in Colitis: in Pursuit of a Novel Therapeutic Target for IBD
McKay, Derek Mark
Committee MemberShutt, Timothy E.
Inflammatory Bowel Disease
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AbstractSince the 1980s, it has been hypothesized that inflammatory bowel disease (IBD) may be tied to insufficient energy production within the intestinal epithelium. In support of this theory, mitochondrial dysfunction has been noted in both IBD patient biopsies and the commonly used dextran sodium sulfate (DSS) murine colitis model. While relatively unexamined in human IBD or animal colitis contexts, evidence obtained from neurological and cardiovascular disease models has shown that unbalanced mitochondrial dynamics, favouring excessive mitochondrial fission, can promote mitochondrial dysfunction and disease. Furthermore, targeted inhibition of two mediators of this maladaptive process, dynamin related protein-1 (DRP1) and mitochondrial fission protein-1 (Fis1), by the novel peptide: P110, has shown therapeutic benefit in both neurodegenerative and cardiovascular disease models. Therefore, previous observations of mitochondrial dysfunction in IBD patients and murine colitis models may be tied to excessive mitochondrial fission, with inhibition of this process by P110 highlighting a potential target for IBD. To test this hypothesis, this study sought to: i) develop protocols for the assessment of mitochondrial function within a murine intestinal epithelial cell line (IEC4.1), ii) apply these protocols and other techniques to identify the consequences of DSS±P110 on IEC4.1 mitochondrial function, morphology and polarization state and iii) systemically deliver P110 in DSS and DNBS murine colitis models to determine if inhibition of excessive mitochondrial fission could exert anti-colitic benefit. Utilizing the developed O2k protocols, we found that DSS induced functional defects in IEC4.1 mitochondria, with P110 co-treatment mitigating some of the observed mitochondrial functional defects. Prophylactic and systemic administration of P110 was found to reduce macroscopic characteristics of both DSS and DNBS colitis in mice. Interestingly, these macroscopic improvements occurred despite limited changes to the assessed inflammatory markers, suggesting similar disease burden between DSS/DNBS+P110 and their disease counterparts. Results obtained from both the cellular and murine colitis models provides evidence that DRP1-Fis1 mediated mitochondrial fission is a feature of these colitis models and that targeting this interaction with P110 yields anti-colitic benefit. Therefore, this interaction could similarly be occurring in IBD patients and prove to be a novel target for future IBD therapeutics.
CitationGoudie, L. (2019). Investigating the Consequences of DRP1 and Fis1 Mediated Mitochondrial Fission in Colitis: in Pursuit of a Novel Therapeutic Target for IBD (Unpublished master's thesis). University of Calgary, Calgary, AB.
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