Mitochondrial gene polymorphisms that protect mice from colitis

Florian Bär, Wiebke Bochmann, Andrea Widok, Kilian Von Medem, Rene Pagel, Misa Hirose, Xinhua Yu, Kathrin Kalies, Peter König, Ruwen Böhm, Thomas Herdegen, Anna T. Reinicke, Jürgen Büning, Hendrik Lehnert, Klaus Fellermann, Saleh Ibrahim, Christian Sina

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Background & Aims Dysregulated energy homeostasis in the intestinal mucosa frequently is observed in patients with ulcerative colitis (UC). Intestinal tissues from these patients have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex, so mitochondrial dysfunction could contribute to the pathogenesis of UC. However, little is known about the mechanisms by which OXPHOS activity could be altered. We used conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex. Methods Colitis was induced in C57BL/6J wild-type (B6.B6) and 3 strains of conplastic mice (B6.NZB, B6.NOD, and B6.AKR) by administration of dextran sodium sulfate or rectal application of trinitrobenzene sulfonate. Colon tissues were collected and analyzed by histopathology, immunohistochemical analysis, and immunoblot analysis; we also measured mucosal levels of adenosine triphosphate (ATP) and reactive oxygen species, OXPHOS complex activity, and epithelial cell proliferation and apoptosis. Results We identified mice with increased mucosal OXPHOS complex activities and levels of ATP. These mice developed less-severe colitis after administration of dextran sodium sulfate or trinitrobenzene sulfonate than mice with lower mucosal levels of ATP. Colon tissues from these mice also had increased enterocyte proliferation and transcription factor nuclear factor-κB activity, which have been shown to protect the mucosal barrier - defects in these processes have been associated with inflammatory bowel disease. Conclusions Variants in mitochondrial DNA that increase mucosal levels of ATP protect mice from colitis. Increasing mitochondrial ATP synthesis in intestinal epithelial cells could be a therapeutic approach for UC.

Original languageBritish English
Pages (from-to)1055-1063.e3
JournalGastroenterology
Volume145
Issue number5
DOIs
StatePublished - Nov 2013

Keywords

  • Conplastic Inbred Mice
  • Energy Metabolism
  • IBD Model
  • Mitochondrial Dysfunction

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