Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis
Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis
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DOI：
10.1038/s41598-019-41933-4
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发表时间：
2019-04-02
影响因子：
4.6
通讯作者：
Walker, Ulrich A.
中科院分区：
文献类型：
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作者：
Jaeger, Veronika K.;Lebrecht, Dirk;Walker, Ulrich A.
活性氧 (ROS) 与间质性肺疾病 (ILD) 的病因有关。我们研究了线粒体中大规模体细胞获得性突变的作用！ DNA (mtDNA) 和连续呼吸链功能障碍是 ROS 形成和肺纤维化的触发因素。对 30 名特发性或结缔组织病 (CTD) 相关 ILD 患者和 13 名对照患者的肺活检中的线粒体进行了分析。我们对 17 名患者的上叶和下叶进行了配对活检。对照样本取自无间质纤维化的肺癌切除术后。丙二醛（ROS 形成的标志物）在 ILD 活检中升高（p = 0.044）。线粒体的活性！与对照组相比，ILD 中呼吸链（细胞色素 C 氧化酶/琥珀酸脱氢酶 [COX/SDH] 比率）降低（中位数 = 0.10）（0.12，p < 0.001），mtDNA 编码的 COX 亚基 2 蛋白的表达标准化为细胞核编码的 COX 亚基 4（COX2/COX4 比率；ILD 中值 = 0.6；对照= 2.2；p < 0.001）。 ILD 中野生型 mtDNA 拷贝数略有升高 (p = 0.088)。常见的 mtDNA 缺失仅在对照中以低水平存在（中位数 = 0%），而在 ILD 中以高水平存在（中位数 = 17%；p
Reactive oxygen species (ROS) are implicated in the aetiology of interstitial lung disease (ILD). We investigated the role of large-scale somatically acquired mutations in mitochondria! DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS-formation and lung fibrosis. Mitochondria were analysed in lung biopsies from 30 patients with idiopathic or connective tissue disease (CTD)related ILD and 13 controls. In 17 patients we had paired biopsies from upper and lower lobes. Control samples were taken from lung cancer resections without interstitial fibrosis. Malondialdehyde, a marker of ROS-formation, was elevated in ILD-biopsies (p = 0.044). The activity of the mitochondria! respiratory chain (cytochrome c-oxidase/succinate dehydrogenase [COX/SDH]-ratio) was depressed in ILD (median = 0.10,) compared with controls (0.12, p < 0.001), as was the expression of mtDNA-encoded COX-subunit-2 protein normalized for the nucleus-encoded COX-subunit-4 (COX2/COX4-ratio; ILD-median = 0.6; controls= 2.2; p < 0.001). Wild-type mtDNA copies were slightly elevated in ILD (p = 0.088). The common mtDNA deletion was only present at low levels in controls (median = 0%) and at high levels in ILD (median = 17%; p