Mechanism of Mitochondrial Dysfunction in COPD

总结 慢性阻塞性肺疾病（COPD）是慢性发病率和死亡率的第三大原因， 在美国（影响估计2300万人）和全球范围内。香烟烟雾（CS） COPD/肺气肿发展的最重要的病因风险因素，导致肺损伤， 有害的反应。这些影响包括线粒体功能障碍（即，还原线粒体膜 潜在的和增加的线粒体活性氧[mtROS]产生），和缺陷的线粒体自噬 （在细胞死亡之前从细胞中去除受损的线粒体）。我们的初步数据显示，CS诱导的 有缺陷的线粒体自噬与功能障碍的线粒体的核周定位和 肺细胞中的端粒-庇护素复合物（一种保护端粒免受DNA损伤的复合物）。我们进一步 显示线粒体从间充质干细胞（MSC）转移到衰老的肺中， 上皮细胞，并防止CS诱导的衰老相关分泌表型， 体外和体内线粒体功能障碍。然而，CS诱导的细胞和分子机制 线粒体自噬损伤和shelterin复合物线粒体易位，以及它们在细胞内的作用 在COPD/肺气肿发展过程中的衰老是未知的。我们假设CS诱导的 线粒体功能障碍通过破坏端粒加帽中的保护屏障而导致线粒体自噬缺陷 蛋白复合物，健康的线粒体转移到受损的肺上皮细胞保护免受CS- 在COPD/肺气肿中诱导损伤性反应。为了验证这些假设，我们将进行以下研究： 在这四年的R 01中有三个具体目标。 (1)确定CS诱导的线粒体功能障碍和缺陷的分子机制 线粒体自噬 (2)确定CS诱导的线粒体功能障碍中shelterin复合物被破坏的机制， 线粒体自噬受损 (3)确定Miro 1（线粒体Rho-GTdR）依赖性的保护和/或恢复作用 新鲜/健康的线粒体转移过程中CS诱导的肺气肿。 这一提议的结果将揭示CS诱导的线粒体损伤的新分子机制。 肺损伤和损伤反应中的功能障碍、庇护复合物破坏和衰老， COPD/肺气肿的发病机制。拟议的研究具有相当大的转化潜力， 他们将确定端粒shelterin复合物和/或 Miro 1介导的线粒体转移可用作治疗糖尿病的新靶点。 COPD/肺气肿的治疗/管理。

SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of chronic morbidity and mortality, both in the United States (affecting an estimated 23 million people) and globally. Cigarette smoke (CS), the most important etiological risk factor for the development of COPD/emphysema, causes lung injurious and damaging responses. These effects include mitochondrial dysfunction (i.e., reduced mitochondrial membrane potential and increased mitochondrial reactive oxygen species [mtROS] generation), and defective mitophagy (removal of damaged mitochondria from a cell prior to cell death). Our preliminary data show that CS-induced defective mitophagy is associated with perinuclear localization of dysfunctional mitochondria and disruption of telomere-shelterin complex (a complex which protects telomeres from DNA damage) in lung cells. We further show that the transfer of mitochondria occurs from mesenchymal stem cells (MSCs) into senesced lung epithelial cells, and protects against CS-induced senescence-associated secretory phenotype and mitochondrial dysfunction in vitro and in vivo. However, the cellular and molecular mechanisms for CS-induced mitophagy impairment and shelterin complex mitochondrial translocation, as well as their roles in cellular senescence during the development of COPD/emphysema are not known. We hypothesize that CS-induced mitochondrial dysfunction leads to defective mitophagy by disrupting the protective shelterin telomere capping protein complex, and that healthy mitochondrial transfer into damaged lung epithelial cells protects against CS- induced injurious responses in COPD/emphysema. To test these hypotheses, we will pursue the following three Specific Aims in this 4-year R01. (1) Determine the molecular mechanisms underlying CS-induced mitochondrial dysfunction and defective mitophagy. (2) Determine the mechanism of disrupted shelterin complex in CS-induced mitochondrial dysfunction and impaired mitophagy. (3) Determine the protective and/or restorative influence of Miro1 (mitochondrial Rho-GTPase)-dependent fresh/healthy mitochondrial transfer during CS-induced pulmonary emphysema. The outcome of this proposal will unravel novel molecular mechanisms for CS-induced mitochondrial dysfunction, shelterin complex disruption, and senescence in lung injurious and damaging responses during the pathogenesis of COPD/emphysema. The proposed studies have considerable translational potential as they will determine the mechanisms whereby possible attenuation of the telomere shelterin complex and/or Miro1-mediated mitochondria transfer can be utilized as novel therapeutic targets for the treatment/management of COPD/emphysema.