Mitochondrial Dysfunction and Metabolic Regulation of the Necroptosis Pathway in COPD and IPF

COPD 和 IPF 中坏死性凋亡途径的线粒体功能障碍和代谢调节

• 批准号: 10172312
• 负责人: Augustine M Choi
• 金额: $ 37.98万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-06 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10172312
• 关键词: Address; Bleomycin; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette Smoker; Cigarette smoke-induced emphysema; Complex; Data; Development; Disease Marker; Distal; Epithelial Cells; Fatty-acid synthase; Fibrosis; Functional disorder; Generations; Genetic; In Vitro; Injury; Kidney; Link; Lung diseases; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial DNA; Necrosis; Organ; Organelles; PTEN-induced putative kinase; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphotransferases; Plasma; Play; Pre-Clinical Model; Process; Protein Kinase; Publishing; Pulmonary Emphysema; Pulmonary Fibrosis; RIPK1 gene; Receptor Activation; Regulation; Role; Severities; Severity of illness; Signal Transduction; Stimulus; Tissues; Urine; cell injury; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung disease; cigarette smoke-induced lung injury; clinical phenotype; exposure to cigarette smoke; heteroplasmy; human disease; in vivo; indium-bleomycin; lipid metabolism; mitochondrial dysfunction; response; urinary

Abstract Fibrosis and emphysema represent divergent clinical phenotypes that emerge during the pathogenesis of chronic lung diseases induced by cigarette smoke (CS). We have uncovered Udistinct mitochondrial and metabolic pathways in response to injurious stimuli that may underlie divergent pathways leading to fibrosis or emphysema outcomesU. Mitochondria are key organelles that regulate metabolism and energy generation, with complex processes governing their dynamics (fusion, fission), and turnover (mitophagy). Mitochondrial dysfunction is an emerging mechanism underlying the pathogenesis of many human diseases including COPD and IPF. We have demonstrated that mitochondrial dysfunction mediates CS-induced epithelial cell injury/emphysema development, and bleomycin (BLM)-induced pulmonary fibrosis; and interestingly, that genetic deficiency in the critical mitophagy regulator PTEN-induced putative kinase-1 (PINK1) is UprotectiveU in preclinical models of CS- induced emphysema while UdeleteriousU in BLM-induced pulmonary fibrosis. Moreover, PINK1-dependent mitophagy was linked to the activation of receptor-interacting protein kinase-3 (RIPK3), a key signaling kinase mediating regulated necrosis (necroptosis). We have published that RIPK3 regulates metabolic processes in organ tissue, including (FA) biosynthetic pathways, and observed that genetic deficiency in fatty acid synthase (FASN), aggravated pulmonary fibrosis. Interestingly, we have found that CS-induced lung injury may trigger systemic responses including injury to distal organs (kidney). Moreover, we and others have found that circulating cell-free (cf)-mtDNA, an established marker of mitochondrial injury and dysfunction, is regulated in plasma or urine of COPD and IPF patients, and that cf-mtDNA sequence variability (heteroplasmy) may play critical roles in the pathogenesis of lung diseases. These intriguing data suggest that mitochondrial pathways influence functional and clinical phenotypes (fibrosis vs. emphysema) in response to CS exposure and led us to propose the following Uhypotheses:U Mitochondrial dysfunction in response to CS can regulate pathways leading to divergent phenotype in COPD or IPF, including the activation of PINK-dependent mitophagy and downstream regulation of RIPK3. Furthermore, key metabolic and mitochondrial signals including mitochondrial fusion/fission and lipid metabolism may determine cellular pathways leading to emphysema or fibrosis. Plasma and/or urinary cf-mtDNA, as well as degree of mitochondrial heteroplasmy, may correlate with severity of IPF and COPD. We will address our hypotheses in the following USpecific Aims:U Specific Aim 1: To determine the functional significance of PINK1-regulated RIPK3 signaling in experimental emphysema and fibrosis. Specific Aim 2: To determine the mechanism(s) by which mitochondrial and metabolic pathways regulate PINK1-RIPK3 signaling in experimental emphysema and fibrosis. Specific Aim 3: To evaluate whether circulating or urinary cf-mtDNA is associated with severity of disease in IPF and COPD.

抽象的 纤维化和肺气肿代表慢性疾病发病机制中出现的不同临床表型 香烟烟雾（CS）引起的肺部疾病。我们发现了独特的线粒体和代谢 对有害刺激作出反应的途径可能是导致纤维化或肺气肿的不同途径的基础 结果U。线粒体是调节新陈代谢和能量产生的关键细胞器，具有复杂的功能 控制其动​​态（融合、裂变）和周转（线粒体自噬）的过程。线粒体功能障碍是 包括 COPD 和 IPF 在内的许多人类疾病发病机制的新兴机制。我们有 证明线粒体功能障碍介导 CS 诱导的上皮细胞损伤/肺气肿 发育和博来霉素（BLM）诱导的肺纤维化；有趣的是，基因缺陷 关键线粒体自噬调节因子 PTEN 诱导的推定激酶 1 (PINK1) 在 CS- 的临床前模型中具有 U 保护作用 诱导肺气肿，而 UdeleteriousU 则诱导 BLM 诱导的肺纤维化。此外，PINK1依赖 线粒体自噬与受体相互作用蛋白激酶 3 (RIPK3) 的激活有关，RIPK3 是一种关键的信号传导激酶 介导调节性坏死（坏死性凋亡）。我们已经发表了 RIPK3 调节代谢过程 器官组织，包括（FA）生物合成途径，并观察到脂肪酸合酶的遗传缺陷 (FASN)，肺纤维化加重。有趣的是，我们发现CS引起的肺损伤可能会引发 全身反应，包括远端器官（肾）损伤。此外，我们和其他人发现 循环游离细胞 (cf)-mtDNA 是线粒体损伤和功能障碍的既定标志物，在 COPD 和 IPF 患者的血浆或尿液，cf-mtDNA 序列变异（异质性）可能发挥作用 在肺部疾病的发病机制中发挥重要作用。这些有趣的数据表明线粒体途径 影响 CS 暴露的功能和临床表型（纤维化与肺气肿），并导致我们 提出以下 U 假设：U 响应 CS 的线粒体功能障碍可以调节导致 COPD 或 IPF 中不同的表型，包括激活 PINK 依赖性线粒体自噬和下游 RIPK3 的调节。此外，关键的代谢和线粒体信号，包括线粒体融合/裂变 脂质代谢可能决定导致肺气肿或纤维化的细胞途径。血浆和/或尿液 cf-mtDNA 以及线粒体异质性程度可能与 IPF 和 COPD 的严重程度相关。我们 将在以下具体目标中解决我们的假设：具体目标 1：确定函数 PINK1 调节的 RIPK3 信号在实验性肺气肿和纤维化中的重要性。具体目标 2： 确定线粒体和代谢途径调节 PINK1-RIPK3 信号传导的机制 实验性肺气肿和纤维化。具体目标 3：评估循环或尿液 cf-mtDNA 是否 与 IPF 和 COPD 疾病的严重程度相关。