title: Mitochondrial gene polymorphisms that protect mice from colitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany; Institute of Anatomy, University of Lübeck, Lübeck, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bär
authors.forename: Wiebke
authors.initials: W
authors.lastname: Bochmann
authors.forename: Andrea
authors.initials: A
authors.lastname: Widok
authors.forename: Kilian
authors.initials: K
authors.lastname: von Medem
authors.forename: Rene
authors.initials: R
authors.lastname: Pagel
authors.forename: Misa
authors.initials: M
authors.lastname: Hirose
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yu
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.forename: Ruwen
authors.initials: R
authors.lastname: Böhm
authors.forename: Thomas
authors.initials: T
authors.lastname: Herdegen
authors.forename: Anna T
authors.initials: AT
authors.lastname: Reinicke
authors.forename: Jürgen
authors.initials: J
authors.lastname: Büning
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.forename: Klaus
authors.initials: K
authors.lastname: Fellermann
authors.forename: Saleh
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D011110:Polymorphism, Genetic / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate
keywords: 2,4-dinitrophenol; ADP; ATP; CS; Conplastic Inbred Mice; DNP; DSS; Energy Metabolism; IBD; IBD Model; Icam-1; Mitochondrial Dysfunction; NF-κB; OXPHOS; TNBS; UC; adenosine diphosphate; adenosine triphosphate; conplastic inbred strain; dextran sodium sulfate; inflammatory bowel disease; intercellular adhesion molekule 1; mDAI; mitochondrial; modified disease activity index; mt; nuclear factor-κB; oxidative phosphorylation; trinitrobenzene sulfonate; ulcerative colitis