title: Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis.
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.
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Surgery, County Council of Östergötland, Linköping, Sweden.
authors.forename: Åsa V
authors.initials: ÅV
authors.lastname: Keita
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Van
authors.initials: V
authors.lastname: Phan
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: McKay
authors.affiliation: Nutrition-Gut-Brain Interactions Research Centre, the Faculty of Medicine, Örebro University, Örebro, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Schoultz
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Lee
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Fernando
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Ronaghan
authors.affiliation: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Dale
authors.initials: D
authors.lastname: Balce
authors.affiliation: Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Yates
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Dicay
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Beck
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Wallace K
authors.initials: WK
authors.lastname: MacNaughton
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Surgery, County Council of Östergötland, Linköping, Sweden.
authors.forename: Johan D
authors.initials: JD
authors.lastname: Söderholm
authors.affiliation: Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada. Electronic address: dmckay@ucalgary.ca.
authors.forename: Derek M
authors.initials: DM
authors.lastname: McKay
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003092:Colitis / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species