Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway
Abstract Programmed necrosis/necroptosis greatly contributes to the pathogenesis of cardiac disorders including myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondria-dependent deat...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07360-2 |
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| author | Teng Sun Jialei Li Shuang Wang Yu Han Xiangyu Tao Min Yuan Zhijie Jing Ting Liu Yuehong Qi Siqi Liu Yanlin Feng Jiasong Chang Lan Zhou Lijuan Gao Jianyun Shi Ruihong Ning Jimin Cao |
| author_facet | Teng Sun Jialei Li Shuang Wang Yu Han Xiangyu Tao Min Yuan Zhijie Jing Ting Liu Yuehong Qi Siqi Liu Yanlin Feng Jiasong Chang Lan Zhou Lijuan Gao Jianyun Shi Ruihong Ning Jimin Cao |
| author_sort | Teng Sun |
| collection | DOAJ |
| description | Abstract Programmed necrosis/necroptosis greatly contributes to the pathogenesis of cardiac disorders including myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondria-dependent death pathway, is poorly understood. Synaptotagmin-1 (Syt1), a Ca2+ sensor, is originally identified in nervous system and mediates synchronous neurotransmitter release. The later findings of Syt1 expressions in many non-neuronal tissues including muscles suggest that Syt1 may exert important functions beyond regulation of neurotransmitter release. Syt1 is highly expressed in cardiomyocytes and has been used as an extracellular molecular probe for SPECT imaging of cardiac cell death in acute myocardial infarction. However, whether Syt1 functions in the pathogenesis of cardiac disorders and what is the molecular etiology have not yet been clarified. We showed here that Syt1 expression was significantly down-regulated in mice I/R injured heart tissues, H2O2-challenged cardiomyocytes and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Enforced expression of Syt1 significantly inhibited myocardial necrotic cell death and interstitial fibrosis, and improved cardiac function in mice subjected to I/R operation. In exploring the underlying mechanisms, we found that Syt1 interacted with Parkin and promoted Parkin-catalyzed CypD ubiquitination, thus inhibited mitochondrial membrane permeability transition pore (mPTP) opening and ultimately suppressed cardiomyocyte necrosis. We further found that Syt1 expression was negatively regulated by miR-193b-3p. MiR-193b-3p regulated cardiomyocyte necrosis and mPTP opening by targeting Syt1. Our present work revealed a novel regulatory model of myocardial necrosis composed of miR-193b-3p, Syt1, Parkin, and CypD, which may provide potential therapeutic targets and strategies for heart protection. |
| format | Article |
| id | doaj-art-518f746f00ba43c4b1eb53d390e016fc |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-518f746f00ba43c4b1eb53d390e016fc2025-01-26T12:54:50ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111610.1038/s41419-025-07360-2Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathwayTeng Sun0Jialei Li1Shuang Wang2Yu Han3Xiangyu Tao4Min Yuan5Zhijie Jing6Ting Liu7Yuehong Qi8Siqi Liu9Yanlin Feng10Jiasong Chang11Lan Zhou12Lijuan Gao13Jianyun Shi14Ruihong Ning15Jimin Cao16Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityLaboratory Animal Center, Shanxi Medical UniversityFirst Hospital of Shanxi Medical UniversityThe Anesthesiology Department of Shanxi Provincial People’s Hospital, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityDepartment of Cardiology, The Second Hospital of Shanxi Medical UniversityKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, School of Basic Medicine, Shanxi Medical UniversityAbstract Programmed necrosis/necroptosis greatly contributes to the pathogenesis of cardiac disorders including myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondria-dependent death pathway, is poorly understood. Synaptotagmin-1 (Syt1), a Ca2+ sensor, is originally identified in nervous system and mediates synchronous neurotransmitter release. The later findings of Syt1 expressions in many non-neuronal tissues including muscles suggest that Syt1 may exert important functions beyond regulation of neurotransmitter release. Syt1 is highly expressed in cardiomyocytes and has been used as an extracellular molecular probe for SPECT imaging of cardiac cell death in acute myocardial infarction. However, whether Syt1 functions in the pathogenesis of cardiac disorders and what is the molecular etiology have not yet been clarified. We showed here that Syt1 expression was significantly down-regulated in mice I/R injured heart tissues, H2O2-challenged cardiomyocytes and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Enforced expression of Syt1 significantly inhibited myocardial necrotic cell death and interstitial fibrosis, and improved cardiac function in mice subjected to I/R operation. In exploring the underlying mechanisms, we found that Syt1 interacted with Parkin and promoted Parkin-catalyzed CypD ubiquitination, thus inhibited mitochondrial membrane permeability transition pore (mPTP) opening and ultimately suppressed cardiomyocyte necrosis. We further found that Syt1 expression was negatively regulated by miR-193b-3p. MiR-193b-3p regulated cardiomyocyte necrosis and mPTP opening by targeting Syt1. Our present work revealed a novel regulatory model of myocardial necrosis composed of miR-193b-3p, Syt1, Parkin, and CypD, which may provide potential therapeutic targets and strategies for heart protection.https://doi.org/10.1038/s41419-025-07360-2 |
| spellingShingle | Teng Sun Jialei Li Shuang Wang Yu Han Xiangyu Tao Min Yuan Zhijie Jing Ting Liu Yuehong Qi Siqi Liu Yanlin Feng Jiasong Chang Lan Zhou Lijuan Gao Jianyun Shi Ruihong Ning Jimin Cao Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway Cell Death and Disease |
| title | Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway |
| title_full | Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway |
| title_fullStr | Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway |
| title_full_unstemmed | Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway |
| title_short | Synaptotagmin-1 attenuates myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway |
| title_sort | synaptotagmin 1 attenuates myocardial programmed necrosis and ischemia reperfusion injury through the mitochondrial pathway |
| url | https://doi.org/10.1038/s41419-025-07360-2 |
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