Mitochondrial Networks: A New Therapeutic Target in Colitis
| Autor: | Lee A. Denson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
ATP
adenosine triphosphate macrophage Mitochondrial Dynamics IEC intestinal epithelial cell TER transepithelial electrical resistance ROS reactive oxygen species GTPase guanosine triphosphatase DNBS medicine Humans DSS dextran sodium sulfate MFN mitofusin Fis1 mitochondrial fission protein-1 Colitis lcsh:RC799-869 Original Research DSS TNF tumor necrosis factor IBD inflammatory bowel disease OPA1 optic atrophy factor 1 Hepatology business.industry Gastroenterology DNBS di-nitrobenzene sulfonic acid medicine.disease Mitochondria IL interleukin inflammation Drp1 dynamin related protein-1 Cancer research LPS lipopolysaccharide qPCR quantitative polymerase chain reaction lcsh:Diseases of the digestive system. Gastroenterology epithelium GM-CSF granulocyte-macrophage colony-stimulating factor business TUNEL deoxyuride-5′-triphosphate biotin nick end labeling |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 2, Pp 426-427 (2020) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background & Aims Mitochondria exist in a constantly remodelling network, and excessive fragmentation can be pathophysiological. Mitochondrial dysfunction can accompany enteric inflammation, but any contribution of altered mitochondrial dynamics (ie, fission/fusion) to gut inflammation is unknown. We hypothesized that perturbed mitochondrial dynamics would contribute to colitis. Methods Quantitative polymerase chain reaction for markers of mitochondrial fission and fusion was applied to tissue from dextran sodium sulfate (DSS)-treated mice. An inhibitor of mitochondrial fission, P110 (prevents dynamin related protein [Drp]-1 binding to mitochondrial fission 1 protein [Fis1]) was tested in the DSS and di-nitrobenzene sulfonic acid (DNBS) models of murine colitis, and the impact of DSS ± P110 on intestinal epithelial and macrophage mitochondria was assessed in vitro. Results Analysis of colonic tissue from mice with DSS-colitis revealed increased mRNA for molecules associated with mitochondrial fission (ie, Drp1, Fis1) and fusion (optic atrophy factor 1) and increased phospho-Drp1 compared with control. Systemic delivery of P110 in prophylactic or treatment regimens reduced the severity of DSS- or DNBS-colitis and the subsequent hyperalgesia in DNBS-mice. Application of DSS to epithelial cells or macrophages caused mitochondrial fragmentation. DSS-evoked perturbation of epithelial cell energetics and mitochondrial fragmentation, but not cell death, were ameliorated by in vitro co-treatment with P110. Conclusions We speculate that the anti-colitic effect of systemic delivery of the anti-fission drug, P110, works at least partially by maintaining enterocyte and macrophage mitochondrial networks. Perturbed mitochondrial dynamics can be a feature of intestinal inflammation, the suppression of which is a potential novel therapeutic direction in inflammatory bowel disease. Graphical abstract |
| Databáze: | OpenAIRE |
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