An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages
Abstract Background 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. Results Differential expre...
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2025-01-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-025-00593-3 |
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| author | Xiaoli Zou Qiqing Huang Tutu Kang Shaoran Shen Chenxi Cao Jianqing Wu |
| author_facet | Xiaoli Zou Qiqing Huang Tutu Kang Shaoran Shen Chenxi Cao Jianqing Wu |
| author_sort | Xiaoli Zou |
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| description | Abstract Background 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. Results 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. Conclusions 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. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| series | Biology Direct |
| spelling | doaj-art-d975bef8fdbc4affb704b88a0191bf6c2025-01-12T12:11:26ZengBMCBiology Direct1745-61502025-01-0120112210.1186/s13062-025-00593-3An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophagesXiaoli Zou0Qiqing Huang1Tutu Kang2Shaoran Shen3Chenxi Cao4Jianqing Wu5Key Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityKey Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Background 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. Results 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. Conclusions 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.https://doi.org/10.1186/s13062-025-00593-3COPDMitochondriaMendelian randomization (MR)Random forest (RF)Least absolute shrinkage and selection operator (LASSO)NDUFS2 |
| spellingShingle | Xiaoli Zou Qiqing Huang Tutu Kang Shaoran Shen Chenxi Cao Jianqing Wu An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages Biology Direct COPD Mitochondria Mendelian randomization (MR) Random forest (RF) Least absolute shrinkage and selection operator (LASSO) NDUFS2 |
| title | An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages |
| title_full | An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages |
| title_fullStr | An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages |
| title_full_unstemmed | An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages |
| title_short | An integrated investigation of mitochondrial genes in COPD reveals the causal effect of NDUFS2 by regulating pulmonary macrophages |
| title_sort | integrated investigation of mitochondrial genes in copd reveals the causal effect of ndufs2 by regulating pulmonary macrophages |
| topic | COPD Mitochondria Mendelian randomization (MR) Random forest (RF) Least absolute shrinkage and selection operator (LASSO) NDUFS2 |
| url | https://doi.org/10.1186/s13062-025-00593-3 |
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