Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis
Abstract The ATP synthase c subunit (c subunit) constitutes the mitochondrial permeability transition pore (mPTP). The extended opening of the mPTP is crucial in the development of various human illnesses. Nevertheless, it remains unclear whether the c subunit regulates the prolonged opening of the...
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BMC
2025-06-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03299-2 |
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| author | Decai Wang Chao Liu Chen Bao Jiannan Hu Ziling Li Xinyue Ma Yunfei Zhu Shuyun Xu |
| author_facet | Decai Wang Chao Liu Chen Bao Jiannan Hu Ziling Li Xinyue Ma Yunfei Zhu Shuyun Xu |
| author_sort | Decai Wang |
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| description | Abstract The ATP synthase c subunit (c subunit) constitutes the mitochondrial permeability transition pore (mPTP). The extended opening of the mPTP is crucial in the development of various human illnesses. Nevertheless, it remains unclear whether the c subunit regulates the prolonged opening of the mPTP to attenuate inflammatory responses in asthma. This study sought to clarify the impact of the c subunit on inflammatory responses and to examine the therapeutic effects of 1,3,8-triazaspiro [4.5] decane derivatives (PP10), a c subunit inhibitor, in human bronchial epithelial (HBE) cells induced by house dust mite (HDM) and lipopolysaccharide (LPS), as well as in a mouse model. The findings indicated that the expression of the c subunit is elevated in asthmatic patients, HDM/LPS-induced HBE cells, and asthmatic mice. The inhibition of the c subunit by PP10 alleviated the prolonged opening of mPTP, then blocked the release of mitochondrial DNA (mtDNA) and cyclic GMP-AMP synthase (cGAS)-interferon response cGAMP interactor (STING) pathway activation in HDM/LPS-induced HBE cells. Furthermore, PP10 decreased the secretion of inflammatory cytokines and ameliorated airway inflammation in HDM/LPS-induced HBE cells and asthmatic animals, respectively. The data collectively suggest that the c subunit triggers an inflammatory response by promoting the sustained opening of mPTP, leading to the activation of the mtDNA-GAS-STING pathway in HDM/LPS-induced HBE cells. Inhibition of the c-subunit attenuates inflammatory responses in HDM/LPS-induced cells or mouse models. Clinical trial number Not applicable. |
| format | Article |
| id | doaj-art-6afbd2cf87844979a20e69d22e506aa6 |
| institution | OA Journals |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-6afbd2cf87844979a20e69d22e506aa62025-08-20T02:37:35ZengBMCRespiratory Research1465-993X2025-06-0126111610.1186/s12931-025-03299-2Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axisDecai Wang0Chao Liu1Chen Bao2Jiannan Hu3Ziling Li4Xinyue Ma5Yunfei Zhu6Shuyun Xu7Department of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract The ATP synthase c subunit (c subunit) constitutes the mitochondrial permeability transition pore (mPTP). The extended opening of the mPTP is crucial in the development of various human illnesses. Nevertheless, it remains unclear whether the c subunit regulates the prolonged opening of the mPTP to attenuate inflammatory responses in asthma. This study sought to clarify the impact of the c subunit on inflammatory responses and to examine the therapeutic effects of 1,3,8-triazaspiro [4.5] decane derivatives (PP10), a c subunit inhibitor, in human bronchial epithelial (HBE) cells induced by house dust mite (HDM) and lipopolysaccharide (LPS), as well as in a mouse model. The findings indicated that the expression of the c subunit is elevated in asthmatic patients, HDM/LPS-induced HBE cells, and asthmatic mice. The inhibition of the c subunit by PP10 alleviated the prolonged opening of mPTP, then blocked the release of mitochondrial DNA (mtDNA) and cyclic GMP-AMP synthase (cGAS)-interferon response cGAMP interactor (STING) pathway activation in HDM/LPS-induced HBE cells. Furthermore, PP10 decreased the secretion of inflammatory cytokines and ameliorated airway inflammation in HDM/LPS-induced HBE cells and asthmatic animals, respectively. The data collectively suggest that the c subunit triggers an inflammatory response by promoting the sustained opening of mPTP, leading to the activation of the mtDNA-GAS-STING pathway in HDM/LPS-induced HBE cells. Inhibition of the c-subunit attenuates inflammatory responses in HDM/LPS-induced cells or mouse models. Clinical trial number Not applicable.https://doi.org/10.1186/s12931-025-03299-2AsthmaAirway epithelial cellsInflammatory responsesMitochondriaATP synthase c subunitMitochondrial permeability transition pore |
| spellingShingle | Decai Wang Chao Liu Chen Bao Jiannan Hu Ziling Li Xinyue Ma Yunfei Zhu Shuyun Xu Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis Respiratory Research Asthma Airway epithelial cells Inflammatory responses Mitochondria ATP synthase c subunit Mitochondrial permeability transition pore |
| title | Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis |
| title_full | Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis |
| title_fullStr | Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis |
| title_full_unstemmed | Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis |
| title_short | Inhibition of the ATP synthase c subunit ameliorates HDM/LPS-induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mPTP-mtDNA-cGAS-STING axis |
| title_sort | inhibition of the atp synthase c subunit ameliorates hdm lps induced inflammatory responses in asthmatic bronchial epithelial cells by blocking the mptp mtdna cgas sting axis |
| topic | Asthma Airway epithelial cells Inflammatory responses Mitochondria ATP synthase c subunit Mitochondrial permeability transition pore |
| url | https://doi.org/10.1186/s12931-025-03299-2 |
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