Role of inner mitochondrial protein OPA1 in mitochondrial dysfunction by tobacco smoking and in the pathogenesis of COPD.
Role of inner mitochondrial protein OPA1 in mitochondrial dysfunction by tobacco smoking and in the pathogenesis of COPD.
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线粒体内蛋白OPA1在吸烟所致线粒体功能障碍和COPD发病机制中的作用
DOI：
10.1016/j.redox.2021.102055
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发表时间：
2021-09
期刊：
影响因子：
11.4
通讯作者：
Rahman I
中科院分区：
文献类型：
--
作者：
Maremanda KP;Sundar IK;Rahman I
慢性肺疾病，如慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）与几种线粒体改变有关。香烟烟雾（CS）改变了线粒体的结构和功能。OPA 1是负责融合事件的主要线粒体内GT3。OPA 1在急性应激和线粒体自噬期间经历从长到短形式的蛋白水解裂解。然而，OPA 1亚型和相关蛋白在CS诱导的线粒体自噬和COPD中的确切作用尚不清楚。采用非吸烟者、吸烟者、COPD和IPF的肺组织来测定OPA 1和相关蛋白的相对表达。此外，我们使用慢性（6个月）CS暴露的小鼠肺来评估OPA 1的状态。使用来自正常和COPD患者的原代肺成纤维细胞和裸鼹鼠（NMR）肺成纤维细胞、人胎肺成纤维细胞（HFL 1）、来自野生型（WT）的小鼠胚胎成纤维细胞、OPA 1-/-、MFN 1和MFN 2-/-来确定CS对OPA 1亚型的影响。使用各种线粒体融合启动子/激活剂（BGP-15、来氟米特、M1）和裂变抑制剂（DRP 1）分别确定它们对OPA 1状态和香烟烟雾提取物（CSE）诱导的肺上皮（BEAS 2B）细胞损伤的影响。Seahorse通量分析仪用于确定这些化合物在有和没有CSE暴露的BEAS 2B细胞中的作用。短OPA 1亚型主要检测和COPD受试者显着增加。在各种细胞系中的急性CSE处理，除了NMR，发现增加长OPA 1亚型向短OPA 1亚型的转化。CSE处理显著增加了所有使用的细胞中的线粒体应激相关蛋白SLP 2。OPA 1相互作用的伙伴，如白藜芦醇（PHB 1和2）也改变了CS曝光的依赖。最后，BGP-15和来氟米特处理能够在用CSE处理的细胞中保留长OPA 1同种型。长OPA 1亚型沿着SLP 2和白蛋白在CS诱导的肺损伤中起关键作用，导致COPD中的线粒体自噬/线粒体功能障碍，其可作为COPD的新的治疗靶点。吸烟是慢性阻塞性肺疾病（COPD）的主要致病因素，COPD与线粒体功能障碍和线粒体自噬改变有关。使用各种策略和模型，包括人样品、小鼠模型和裸鼹鼠成纤维细胞，以确定香烟烟雾和COPD中OPA 1形式的行为。香烟烟雾暴露和COPD患者中，S-OPA 1的肺细胞水平显著增加，沿着SLP-2水平和改变的白蛋白。化合物如BGP-15和来氟米特促进/维持L-OPA 1水平。长OPA 1亚型沿着SLP 2和白蛋白在COPD线粒体自噬/线粒体功能障碍期间烟草烟雾诱导的肺损伤中起关键作用，其可以是COPD的治疗靶点。
Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are linked to several mitochondrial alterations. Cigarette smoke (CS) alters the structure and function of mitochondria. OPA1 is the main inner mitochondrial GTPase responsible for the fusion events. OPA1 undergoes proteolytic cleavage from long to short forms during acute stress and mitophagy. However, the exact role of OPA1 isoforms and related proteins during CS-induced mitophagy and COPD is not clear. Lung tissues from non-smokers, smokers, COPD and IPF were used to determine the relative expression of OPA1 and related proteins. Additionally, we used mouse lungs from chronic (6 months) CS exposure to evaluate the status of OPA1. Primary lung fibroblasts from normal and COPD patients and naked mole rat (NMR) lung fibroblasts, human fetal lung fibroblast (HFL1), mouse embryonic fibroblast from wild type (WT), OPA1−/−, MFN1 and MFN2−/− were used to determine the effect of CS on OPA1 isoforms. Various mitochondrial fusion promoters/activators (BGP-15, leflunomide, M1) and fission inhibitor (DRP1) were used to determine their effect on OPA1 status and cigarette smoke extract (CSE)-induced lung epithelial (BEAS2B) cell damage, respectively. Seahorse flux analyzer was used to determine the effect of these compounds in BEAS2B cells with and without CSE exposure. Short OPA1 isoforms were predominantly detected and significantly increased in COPD subjects. Acute CSE treatment in various cell lines except NMR was found to increase the conversion of long to short OPA1 isoforms. CSE treatment significantly increased mitochondrial stress-related protein SLP2 in all the cells used. OPA1 interacting partners like prohibitins (PHB1 and 2) were also altered depending on the CS exposure. Finally, BGP-15 and leflunomide treatment were able to preserve the long OPA1 isoform in cells treated with CSE. The long OPA1 isoform along with SLP2 and prohibitins play a crucial role in CS-induced lung damage, causing mitophagy/mitochondrial dysfunction in COPD, which may be used as a novel therapeutic target in COPD. Smoking is the main causative factor for Chronic Obstructive Pulmonary Disease (COPD) which is associated with mitochondrial dysfunction and altered mitophagy. Various strategies and models ranging from human samples, mouse models and naked mole rat fibroblasts were used to determine the behavior of the OPA1 forms by cigarette smoke and in COPD. Cigarette smoke exposure and in patients with COPD the lung cellular levels of S-OPA1 are significantly increased, along with SLP-2 levels with altered prohibitins. Compounds like BGP-15 and leflunomide promoted/maintained the L-OPA1 levels. Long OPA1 isoforms along with SLP2 and prohibitins play a crucial role in tobacco smoke-induced lung damage during mitophagy/mitochondrial dysfunction in COPD, which can be a therapeutic target in COPD.
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影响因子：
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影响因子：
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作者：
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DOI：
10.1152/ajplung.00155.2013
发表时间：
2014-05-01
影响因子：
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作者：
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