Metabolic dysfunction regulates mitophagy-dependent necroptosis in COPD

项目摘要 慢性阻塞性肺疾病（COPD）的发病机制，主要是 与吸烟（CS）相关的疾病，包括肺气肿和支气管炎，尚不清楚。我们的出版 研究表明，自噬，一种溶酶体依赖的细胞器降解途径， 蛋白质，代表了一个主要的细胞和组织的反应，CS暴露，在实验和人类 慢性阻塞性肺病新兴的研究表明，自噬，虽然作为一种细胞生存过程， 在复杂疾病中发挥稳态或有害作用。我们的研究首次证明 自噬和线粒体自噬（mitophagy）在COPD实验模型中的有害作用。 线粒体自噬调节因子PINK1基因缺陷的小鼠对实验性COPD有抵抗力。我们 发现CS诱导的线粒体自噬响应于线粒体功能障碍激活程序化的 上皮细胞死亡，特别是细胞死亡的坏死性凋亡模式。我们的初步研究表明， 暴露可破坏代谢途径，包括氧化磷酸化（OXPHOS）失调， 抑制脂肪酸（FA）合成。因此，我们提出以下假设：CS暴露导致 上皮细胞代谢破坏和FA合成受损，导致线粒体功能障碍， PINK1依赖性线粒体自噬的激活。线粒体自噬反过来驱动一种依赖于 坏死性凋亡的激活这种线粒体自噬依赖性坏死性凋亡途径的激活是对 代谢和线粒体功能障碍可能会对气道功能和肺气肿的结果产生不利影响， CS诱导的COPD发病机制。为了验证这一假设，我们将讨论三个具体目标：具体目标1： 确定CS诱导肺线粒体自噬的机制。具体目标2：确定 受损的OXPHOS和FA合成对线粒体动力学和生物发生调节的影响， 对实验性COPD的影响具体目的3：确定CS对细胞坏死性凋亡的调节， 及其对COPD实验模型肺功能损害的影响。

PROJECT SUMMARY The mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD), primarily associated with cigarette smoking (CS), including emphysema and bronchitis, remain unclear. Our published studies have suggested that autophagy, a lysosome-dependent pathway for the degradation of organelles and proteins, represents a major cellular and tissue response to CS exposure, in both experimental and human COPD lung. Emerging studies suggest that autophagy, while well established as a cellular survival process, can exert homeostatic or detrimental effects in complex diseases. Our studies were the first to demonstrate deleterious effects of autophagy and mitochondrial autophagy (mitophagy) in experimental models of COPD. Mice genetically deficient in the mitophagy regulator PINK1 were resistant to experimental COPD. We discovered that mitophagy induced by CS in response to mitochondrial dysfunction activates programmed epithelial cell death, in particular the necroptosis mode of cell death. Our Preliminary Studies indicate that CS exposure can disrupt metabolic pathways, including dysregulation of oxidative phosphorylation (OXPHOS) and inhibition of fatty acid (FA) synthesis. Hence, we put forth the following Hypothesis: CS exposure causes epithelial cell metabolic disruption and impaired FA synthesis that causes mitochondrial dysfunction, leading to activation of PINK1-dependent mitophagy. Mitophagy in turn drives a pro-pathogenic mechanism dependent on the activation of necroptosis. Activation of this mitophagy-dependent necroptosis pathway in response to metabolic and mitochondrial dysfunction may adversely affect airway function and emphysema outcomes during CS-induced COPD pathogenesis. To test this hypothesis, we will address three Specific Aims: Specific Aim 1: To determine the mechanisms by which CS induces mitophagy in the lung. Specific Aim 2: To determine the effect of impaired OXPHOS and FA synthesis on the regulation of mitochondrial dynamics and biogenesis and their impact on experimental COPD. Specific Aim 3: To determine the regulation of cellular necroptosis by CS, and its impact on lung functional impairment in experimental models of COPD.