Zou Xiaoli, Huang Qiqing, Kang Tutu, Shen Shaoran, Cao Chenxi, Wu Jianqing
Key Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
Biol Direct. 2025 Jan 9;20(1):4. doi: 10.1186/s13062-025-00593-3.
Despite the increasing body of evidence that mitochondrial activities implicate in chronic obstructive pulmonary disease (COPD), we are still far from a causal-logical and mechanistic understanding of the mitochondrial malfunctions in COPD pathogenesis.
Differential expression genes (DEGs) from six publicly available bulk human lung tissue transcriptomic datasets of COPD patients were intersected with the known mitochondria-related genes from MitoCarta3.0 to obtain mitochondria-related DEGs associated with COPD (MitoDEGs). The 32 hub MitoDEGs identified from protein-protein interaction (PPI) networks demonstrated superior overall diagnostic efficacy to non-hub MitoDEGs. Random forest (RF) analysis, least absolute shrinkage and selection operator (LASSO) regression, and Mendelian Randomization (MR) analysis of hub MitoDEGs further nominated NDUFS2, CAT, and MRPL2 as causal MitoDEGs for COPD, whose predominate expressions in pulmonary macrophages were revealed by an independent single-cell transcriptomic dataset of COPD human lungs. Finally, NDUFS2 was evaluated as the top-ranked contributor to COPD in the nomogram model and its downregulation in pulmonary macrophages could result in pro-inflammatory secretion, enhanced intercellular communications, whereas depressed phagocytosis of macrophages as revealed by gene set variation analysis (GSVA) and cell-cell interaction (CCI) analysis of single-cell transcriptomic dataset of COPD human lungs, which was later confirmed in COPD mouse model and macrophage cell lines.
Our study established the causal linkage between mitochondrial malfunctions and COPD, providing a potential therapeutic avenue to alleviate pulmonary inflammation accounting for COPD by targeting mitochondria-related genes. NDUFS2, a canonical component of mitochondrial electron respiratory chain, was highlighted instrumental for the susceptibility of risk-exposed individuals to COPD.
尽管越来越多的证据表明线粒体活动与慢性阻塞性肺疾病（COPD）有关，但我们对COPD发病机制中线粒体功能障碍的因果逻辑和机制仍知之甚少。
将来自六个公开可用的COPD患者大容量人肺组织转录组数据集的差异表达基因（DEG）与来自MitoCarta3.0的已知线粒体相关基因进行交叉分析，以获得与COPD相关的线粒体相关DEG（MitoDEG）。从蛋白质-蛋白质相互作用（PPI）网络中鉴定出的32个核心MitoDEG显示出比非核心MitoDEG更高的总体诊断效能。对核心MitoDEG进行随机森林（RF）分析、最小绝对收缩和选择算子（LASSO）回归以及孟德尔随机化（MR）分析，进一步将NDUFS2、CAT和MRPL2指定为COPD的因果MitoDEG，COPD患者人肺的独立单细胞转录组数据集显示它们在肺巨噬细胞中占主导地位。最后，在列线图模型中，NDUFS2被评估为COPD的首要贡献因素，通过对COPD患者人肺单细胞转录组数据集的基因集变异分析（GSVA）和细胞-细胞相互作用（CCI）分析发现，其在肺巨噬细胞中的下调会导致促炎分泌、细胞间通讯增强，而巨噬细胞的吞噬作用受到抑制，这一点在COPD小鼠模型和巨噬细胞系中得到了证实。
我们的研究建立了线粒体功能障碍与COPD之间的因果联系，为通过靶向线粒体相关基因减轻COPD的肺部炎症提供了一条潜在的治疗途径。NDUFS2是线粒体电子呼吸链的一个典型组成部分，被认为是风险暴露个体易患COPD的重要因素。
