Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis.

TitleTargeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis.
Publication TypeJournal Article
Year of Publication2014
AuthorsWang, A, Keita, ÅV, Phan, V, McKay, CM, Schoultz, I, Lee, J, Murphy, MP, Fernando, M, Ronaghan, N, Balce, D, Yates, R, Dicay, M, Beck, PL, MacNaughton, WK, Söderholm, JD, McKay, DM
JournalAm J Pathol
Volume184
Issue9
Pagination2516-27
Date Published2014 Sep
ISSN1525-2191
KeywordsAnimals, Antioxidants, Colitis, Disease Models, Animal, Humans, Intestinal Mucosa, Male, Mice, Mice, Inbred BALB C, Mitochondria, Permeability, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction
Abstract

Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coli with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and translocation of E. coli across epithelia and control colonic biopsy specimens, which was more striking in Crohn's disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases.

DOI10.1016/j.ajpath.2014.05.019
Alternate JournalAm. J. Pathol.
Citation Key10.1016/j.ajpath.2014.05.019
PubMed ID25034594
PubMed Central IDPMC4188172
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
MPO 126005 / / Canadian Institutes of Health Research / Canada