Gastrointestinal Research Group (GIRG) and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary.
Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary.
Cell Mol Gastroenterol Hepatol. 2020;10(2):287-307. doi: 10.1016/j.jcmgh.2020.04.004. Epub 2020 Apr 13.
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.
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.
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.
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.
线粒体存在于不断重塑的网络中，过度碎片化可能是病理生理现象。线粒体功能障碍可能伴随着肠炎症，但改变线粒体动力学（即分裂/融合）对肠道炎症的任何贡献尚不清楚。我们假设，线粒体动力学的紊乱会导致结肠炎。
用定量聚合酶链反应检测葡聚糖硫酸钠（DSS）处理的小鼠组织中线粒体分裂和融合的标志物。用线粒体分裂抑制剂 P110（阻止动力相关蛋白[Drp]-1与线粒体分裂 1 蛋白[Fis1]结合）在 DSS 和二硝基苯磺酸（DNBS）诱导的小鼠结肠炎模型中进行测试，并在体外评估 DSS ± P110 对肠道上皮细胞和巨噬细胞线粒体的影响。
分析 DSS 结肠炎小鼠结肠组织发现，与对照相比，与线粒体分裂（即 Drp1、Fis1）和融合（光萎缩因子 1）相关的分子的 mRNA 增加，磷酸化 Drp1 增加。在预防或治疗方案中系统给予 P110 可减轻 DSS 或 DNBS 结肠炎的严重程度，以及随后 DNBS 小鼠的痛觉过敏。上皮细胞或巨噬细胞中 DSS 的应用导致线粒体碎片化。DSS 引起的上皮细胞能量代谢和线粒体碎片化的紊乱，但不是细胞死亡，在体外用 P110 共同处理后得到改善。
我们推测，系统给予抗分裂药物 P110 的抗结肠炎作用至少部分是通过维持肠上皮细胞和巨噬细胞的线粒体网络来实现的。线粒体动力学的紊乱可能是肠道炎症的一个特征，抑制这种动力学可能是炎症性肠病的一个潜在的新治疗方向。
