Han Jie, Yu Chunhua, Souza Rhonda F, Theiss Arianne L
Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States.
Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Cell Signal. 2014 Oct;26(10):2086-95. doi: 10.1016/j.cellsig.2014.06.006. Epub 2014 Jun 26.
Mitochondrial dysfunction in intestinal epithelial cells (IEC) is thought to precede the onset of inflammatory bowel diseases (IBD). Expression of Prohibitin 1 (PHB), a mitochondrial protein required for optimal electron transport chain (ETC) activity, is decreased in mucosal biopsies during active and inactive IBD. In addition to its activities as a transcription factor, Signal Transducer and Activator of Transcription 3 (Stat3) resides in the mitochondria of cells where phosphorylation at S727 is required for optimal ETC activity and protects against stress-induced mitochondrial dysfunction. Here, we show that PHB overexpression protects against mitochondrial stress and apoptosis of cultured IECs induced by TNFα, which is a pro-inflammatory cytokine involved in IBD pathogenesis. Expression of pS727-Stat3 dominant negative eliminates protection by PHB against TNFα-induced mitochondrial stress and apoptosis. PHB interacts with pS727-Stat3 in the mitochondria of cultured IECs and in colonic epithelium from wild-type mice. Our data suggest a protective role of PHB that is dependent on pS727-Stat3 to prevent mitochondrial dysfunction in IECs. Reduced levels of PHB during IBD may be an underlying factor promoting mitochondrial dysfunction of the intestinal epithelium.
肠道上皮细胞（IEC）中的线粒体功能障碍被认为先于炎症性肠病（IBD）的发作。 prohibitin 1（PHB）是一种线粒体蛋白，是最佳电子传递链（ETC）活性所必需的，在活动期和非活动期IBD的黏膜活检中其表达降低。除了作为转录因子的活性外，信号转导和转录激活因子3（Stat3）存在于细胞的线粒体中，其中S727位点的磷酸化是最佳ETC活性所必需的，并能防止应激诱导的线粒体功能障碍。在这里，我们表明PHB的过表达可保护培养的IECs免受TNFα诱导的线粒体应激和凋亡，TNFα是一种参与IBD发病机制的促炎细胞因子。pS727-Stat3显性阴性的表达消除了PHB对TNFα诱导的线粒体应激和凋亡的保护作用。PHB在培养的IECs线粒体和野生型小鼠结肠上皮中与pS727-Stat3相互作用。我们的数据表明PHB具有依赖于pS727-Stat3的保护作用，以防止IECs中的线粒体功能障碍。IBD期间PHB水平降低可能是促进肠上皮线粒体功能障碍的潜在因素。
