Mechanism of Mitochondrial Dysfunction in COPD

摘要 慢性阻塞性肺疾病(COPD)是导致慢性发病率和死亡率的第三大原因， 在美国(估计有2300万人受到影响)和全球都是如此。香烟烟雾(CS)， 慢性阻塞性肺疾病/肺气肿的最重要的病因危险因素，导致肺损伤和 破坏性的反应。这些影响包括线粒体功能障碍(即线粒体膜减少 潜在的和增加的线粒体活性氧[mtROS]生成)，以及有丝分裂缺陷 (在细胞死亡前将受损的线粒体从细胞中移除)。我们的初步数据显示，CS诱导 吞丝体缺陷与功能障碍线粒体的核周定位和信号转导中断有关 肺细胞中的端粒-保护素复合体(保护端粒免受DNA损伤的复合体)。我们进一步 表明线粒体从间充质干细胞(MSCs)转移到衰老的肺中 对CS诱导的衰老相关分泌表型和 体内和体外线粒体功能障碍。然而，CS诱导的细胞和分子机制 线粒体复合体易位中的丝裂原损伤和保护及其在细胞中的作用 COPD/肺气肿发展过程中的衰老尚不清楚。我们假设CS诱导的 线粒体功能障碍通过破坏端粒顶端的保护性屏障而导致有丝分裂缺陷 蛋白质复合体，而健康的线粒体转移到受损的肺上皮细胞可以预防CS- 在慢性阻塞性肺疾病/肺气肿中诱导损伤反应。为了验证这些假设，我们将进行以下工作 在这个4年的R01中有三个具体的目标。 (1)确定CS诱导线粒体功能障碍和缺陷的分子机制 有丝分裂。 (2)确定CS诱导的线粒体功能障碍中保护蛋白复合体破坏的机制。 吞丝分裂功能受损。 (3)确定MIRO1(线粒体Rho-GTP酶)依赖的保护和/或修复影响 CS诱导的肺气肿期间新鲜/健康的线粒体转移。 这一提议的结果将揭开CS诱导线粒体的新的分子机制 肺损伤和损伤性反应中的功能障碍、庇护复合体中断和衰老 COPD/肺气肿的发病机制。拟议的研究具有相当大的翻译潜力，因为 他们将确定端粒保护复合体和/或端粒可能减弱的机制 Miro1介导的线粒体转移可作为新的治疗靶点。 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.