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

摘要 纤维化和肺气肿是慢性阻塞性肺疾病发病过程中出现的不同临床表型。 吸烟(CS)引起的肺部疾病。我们发现了不同的线粒体和新陈代谢 对损伤性刺激的反应通路可能是导致纤维化或肺气肿的不同通路的基础 结果是U。线粒体是调节新陈代谢和能量产生的关键细胞器，具有复合体 控制其动力学(融合、裂变)和周转(吞丝分裂)的过程。线粒体功能障碍是一种 包括COPD和IPF在内的许多人类疾病的发病机制正在形成。我们有 线粒体功能障碍介导CS诱导的上皮细胞损伤/肺气肿 发展和博莱霉素(BLM)诱导的肺纤维化；有趣的是， 关键的吞噬丝裂原调节因子PTEN诱导的假定蛋白-1(PINK1)在临床前CS-1模型中起保护作用。 在博莱姆诱导的肺纤维化模型中，乌拉地尔可诱发肺气肿。此外，PINK1依赖于 有丝分裂与受体相互作用蛋白激酶-3(RIPK3)的激活有关，RIPK3是一种关键的信号通路 调节坏死(坏死性下垂)。我们已经发表了RIPK3在体内调节代谢过程 器官组织，包括(FA)生物合成途径，并观察到脂肪酸合成酶的遗传缺陷 (FASN)，加重肺纤维化。有趣的是，我们发现CS诱导的肺损伤可能引发 全身反应，包括对远端器官(肾脏)的损伤。此外，我们和其他人发现 循环无细胞(Cf)-mtDNA是线粒体损伤和功能障碍的一个公认的标志，在 COPD和IPF患者血浆或尿液以及cf-mtDNA序列变异性(异质性)可能起作用 在肺部疾病发病机制中的关键作用。这些耐人寻味的数据表明线粒体途径 CS暴露对功能和临床表型(纤维化与肺气肿)的影响，并导致我们 提出以下假设：U线粒体功能障碍对CS的反应可以调节通路 到COPD或IPF的不同表型，包括激活粉红色依赖的有丝分裂和下游 RIPK3的监管。此外，包括线粒体融合/分裂在内的关键代谢和线粒体信号 脂质代谢可能决定了导致肺气肿或纤维化的细胞途径。血浆和/或尿液 Cf-mtDNA和线粒体异质性程度可能与IPF和COPD的严重程度相关。我们 我们将在以下具体目标中解决我们的假设：具体目标1：确定功能 PINK1调节的RIPK3信号在实验性肺气肿和纤维化中的意义。具体目标2： 确定线粒体和代谢途径调节PINK1-RIPK3信号的机制(S) 实验性肺气肿和纤维化。具体目标3：评估循环或尿cf-mtDNA是否 与IPF和COPD的病情严重程度相关。

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.