Mitochondrial Dysfunction and Mitophagy in Ileitis

项目总结 尽管在人类克罗恩病(CD)的肠上皮细胞中发现线粒体功能障碍 和溃疡性结肠炎患者，针对线粒体功能障碍的炎症性肠病(IBD)治疗 是目前所缺乏的。人们普遍认为，细胞内的线粒体池是通过移除来维持的 通过称为有丝分裂的选择性自噬来修复受损的线粒体。有丝分裂可能是特别重要的 富含线粒体的肠道分泌细胞(潘氏、杯状、内分泌)的功能 维持耗能的分泌功能，但这一点尚未得到证实。潘氏细胞功能障碍 可以由自噬缺陷驱动的CD患者的一部分被证实。然而，这种机制 线粒体应激导致炎症和潘氏细胞异常的原因尚不清楚。 Prohibitin 1(PHB1)是线粒体内膜(IMM)的主要组成蛋白。 调节电子传递链功能，对三磷酸腺苷的产生很重要。我们已经培育出了带有绒毛蛋白的小鼠- CRERT2可诱导肠上皮细胞特异性缺失PHB1基因(PHB1∆IEC)并显示 这些小鼠表现为自发性回肠炎，先于线粒体功能障碍和早期潘氏细胞缺陷 在PHB1缺失后。PHB1∆IEC小鼠的潘氏细胞异常使人联想到潘氏细胞缺陷的小鼠 自噬。我们的中心假设是线粒体功能障碍并随后抑制有丝分裂 由于PHB1在肠道上皮细胞中的丢失而导致潘氏细胞功能障碍和回肠炎。我们将追查3个 具体目的是验证这一假说：1.确定PHB1在线粒体功能障碍和自发性中的作用 回肠炎，2.确定PHB1在有丝分裂诱导中的作用，以及3.确定Paneth细胞是否表现为 线粒体功能障碍与线粒体靶向治疗是否能对抗炎症 克罗恩回肠炎。长期目标是确定以线粒体功能障碍为靶点是否 IBD的有效治疗策略。

Project summary Although mitochondrial dysfunction is demonstrated in the intestinal epithelium of human Crohn's disease (CD) and ulcerative colitis patients, inflammatory bowel disease (IBD) therapies targeting mitochondrial dysfunction are currently lacking. It is widely appreciated that the intracellular mitochondrial pool is maintained by removal of damaged mitochondria via selective autophagy called mitophagy. Mitophagy may be especially important for the function of intestinal secretory cells (Paneth, goblet, enteroendocrine) which are mitochondria-rich to sustain energy-expending secretory functions, but this has yet to be demonstrated. Paneth cell dysfunction that can be driven by autophagy defects is demonstrated in a subset of CD patients. However, the mechanism whereby mitochondrial stress contributes to inflammation and Paneth cell abnormalities are unknown. Prohibitin 1 (PHB1) is the major component protein of the inner mitochondrial membrane (IMM) where it regulates electron transport chain function important for ATP production. We have generated mice with Villin- CreERT2 inducible intestinal epithelial cell (IEC)-specific deletion of the PHB1 gene (PHB1∆IEC) and show that these mice exhibit spontaneous ileitis preceded by mitochondrial dysfunction and Paneth cell defects early after PHB1 deletion. Paneth cell abnormalities in PHB1∆IEC mice are reminiscent of mice deficient in Paneth cell autophagy. Our central hypothesis is that mitochondrial dysfunction with subsequent inhibition of mitophagy caused by loss of PHB1 in the intestinal epithelium leads to Paneth cell dysfunction and ileitis. We will pursue 3 specific aims to test this hypothesis: 1. Define the role of PHB1 in mitochondrial dysfunction and spontaneous ileitis, 2. Determine the role of PHB1 in mitophagy induction, and 3. Define whether Paneth cells manifest mitochondrial dysfunction and whether mitochondrial-targeted therapy combats inflammation in patients with Crohn's ileitis. The long-term objective is to determine whether targeting mitochondrial dysfunction is an effective therapeutic strategy for IBD.