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Perturbed Mitochondrial Dynamics Is a Novel Feature of Colitis That Can Be Targeted to Lessen Disease.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.2 ) Pub Date : 2020-04-13 , DOI: 10.1016/j.jcmgh.2020.04.004
Nicole L Mancini 1 , Luke Goudie 2 , Warren Xu 2 , Rasha Sabouny 3 , Sruthi Rajeev 1 , Arthur Wang 1 , Nicolas Esquerre 4 , Ala Al Rajabi 1 , Timothy S Jayme 1 , Erik van Tilburg Bernandes 5 , Yasmin Nasser 4 , José G P Ferraz 4 , Timothy Shutt 3 , Jane Shearer 6 , Derek M McKay 1
Affiliation  

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.



中文翻译:

扰动的线粒体动力学是结肠炎的一种新功能,可以减少疾病。

背景与目标

线粒体存在于不断重塑的网络中,过度的破碎可能是病理生理学。线粒体功能障碍可伴有肠道炎症,但线粒体动力学改变(即裂变/融合)对肠道炎症的任何贡献尚不清楚。我们假设扰动的线粒体动力学将导致结肠炎。

方法

定量聚合酶链反应的线粒体裂变和融合标志物被应用于葡聚糖硫酸钠(DSS)处理小鼠的组织。在鼠结肠炎的DSS和二硝基苯磺酸(DNBS)模型中测试了线粒体裂变抑制剂P110(防止与动力蛋白有关的蛋白[Drp] -1与线粒体裂变1蛋白[Fis1]结合),以及体外评估肠上皮和巨噬细胞线粒体的DSS±P110。

结果

与DSS结肠炎小鼠相比,结肠组织的分析显示与线粒体裂变(即Drp1,Fis1)和融合(视神经萎缩因子1)相关的分子的mRNA增加,而磷酸Drp1与对照组相比增加。在预防或治疗方案中全身递送P110可降低DSS或DNBS结肠炎的严重程度,以及随后的DNBS小鼠痛觉过敏。将DSS应用于上皮细胞或巨噬细胞会导致线粒体片段化。通过与P110进行体外共同治疗,可改善DSS引起的上皮细胞能量紊乱和线粒体破碎,但不会导致细胞死亡。

结论

我们推测,抗裂变药物P110全身递送的抗结肠炎作用至少部分通过维持肠上皮细胞和巨噬细胞线粒体网络起作用。线粒体动力学紊乱可能是肠道炎症的特征,其抑制是炎症性肠病的潜在新治疗方向。

更新日期:2020-04-13
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