TY - JOUR
T1 - Mitochondrial gene polymorphisms that protect mice from colitis
AU - Bär, Florian
AU - Bochmann, Wiebke
AU - Widok, Andrea
AU - Von Medem, Kilian
AU - Pagel, Rene
AU - Hirose, Misa
AU - Yu, Xinhua
AU - Kalies, Kathrin
AU - König, Peter
AU - Böhm, Ruwen
AU - Herdegen, Thomas
AU - Reinicke, Anna T.
AU - Büning, Jürgen
AU - Lehnert, Hendrik
AU - Fellermann, Klaus
AU - Ibrahim, Saleh
AU - Sina, Christian
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84886774010&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2013.07.015
DO - 10.1053/j.gastro.2013.07.015
M3 - Journal articles
AN - SCOPUS:84886774010
SN - 0016-5085
VL - 145
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -