MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes
Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS rem...
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| Language: | English |
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Elsevier
2025-07-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001946 |
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| author | Xiangyu Li Faliang Zhan Guangfeng Qiu Peng Lu Zihao Shen Yuanpu Qi Minchao Wu Mingyu Chu Jia Feng Ziang Wen Xin Yao Ao Wang Wanjun Jin Xiao Zhang Junjie Liao Jialin Zhang Meijuan Song Wei Wang Xiaowei Wang |
| author_facet | Xiangyu Li Faliang Zhan Guangfeng Qiu Peng Lu Zihao Shen Yuanpu Qi Minchao Wu Mingyu Chu Jia Feng Ziang Wen Xin Yao Ao Wang Wanjun Jin Xiao Zhang Junjie Liao Jialin Zhang Meijuan Song Wei Wang Xiaowei Wang |
| author_sort | Xiangyu Li |
| collection | DOAJ |
| description | Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS remains unclear. Here, we identify MOTS-c as a critical mediator of endothelial protection against LIRI through MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress. Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport. RNA sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs). Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms. Our findings establish MOTS-c as a dual-function molecule—acting via ROS-CK2A-MYH9 signaling to activate nuclear antioxidant defenses and serving as a prognostic biomarker for CPB-related complications. This study bridges mitochondrial dynamics, nuclear transcriptional regulation, and clinical outcomes, offering novel preventive avenues for IRI-associated pathologies. |
| format | Article |
| id | doaj-art-0b72c60833724231bbfeb9cf33c82f3e |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-0b72c60833724231bbfeb9cf33c82f3e2025-08-20T02:26:09ZengElsevierRedox Biology2213-23172025-07-018410368110.1016/j.redox.2025.103681MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genesXiangyu Li0Faliang Zhan1Guangfeng Qiu2Peng Lu3Zihao Shen4Yuanpu Qi5Minchao Wu6Mingyu Chu7Jia Feng8Ziang Wen9Xin Yao10Ao Wang11Wanjun Jin12Xiao Zhang13Junjie Liao14Jialin Zhang15Meijuan Song16Wei Wang17Xiaowei Wang18Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiothoracic Surgery, Yili Friendship Hospital, Yining, ChinaDepartment of Respiratory and Critical Care Medicine, Yili Friendship Hospital, Yining, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; Corresponding author.Mazankowski Alberta Heart Institute, University of Alberta, Canada; Corresponding author.Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; Department of Cardiovascular Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China; Corresponding author. Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS remains unclear. Here, we identify MOTS-c as a critical mediator of endothelial protection against LIRI through MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress. Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport. RNA sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs). Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms. Our findings establish MOTS-c as a dual-function molecule—acting via ROS-CK2A-MYH9 signaling to activate nuclear antioxidant defenses and serving as a prognostic biomarker for CPB-related complications. This study bridges mitochondrial dynamics, nuclear transcriptional regulation, and clinical outcomes, offering novel preventive avenues for IRI-associated pathologies.http://www.sciencedirect.com/science/article/pii/S2213231725001946Acute respiratory distress syndromeCardiopulmonary bypassIschemia reperfusion injuryOxidative stressMOTS-cMYH9 |
| spellingShingle | Xiangyu Li Faliang Zhan Guangfeng Qiu Peng Lu Zihao Shen Yuanpu Qi Minchao Wu Mingyu Chu Jia Feng Ziang Wen Xin Yao Ao Wang Wanjun Jin Xiao Zhang Junjie Liao Jialin Zhang Meijuan Song Wei Wang Xiaowei Wang MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes Redox Biology Acute respiratory distress syndrome Cardiopulmonary bypass Ischemia reperfusion injury Oxidative stress MOTS-c MYH9 |
| title | MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes |
| title_full | MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes |
| title_fullStr | MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes |
| title_full_unstemmed | MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes |
| title_short | MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes |
| title_sort | mots c attenuates lung ischemia reperfusion injury via myh9 dependent nuclear translocation and transcriptional activation of antioxidant genes |
| topic | Acute respiratory distress syndrome Cardiopulmonary bypass Ischemia reperfusion injury Oxidative stress MOTS-c MYH9 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725001946 |
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