Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury
Abstract The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemi...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202414960 |
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| author | Anqi Luo Rui Wang Jingwen Gong Shuting Wang Chuan Yun Zongcun Chen Yanan Jiang Xiaoquan Liu Haofu Dai Haochen Liu Yunsi Zheng |
| author_facet | Anqi Luo Rui Wang Jingwen Gong Shuting Wang Chuan Yun Zongcun Chen Yanan Jiang Xiaoquan Liu Haofu Dai Haochen Liu Yunsi Zheng |
| author_sort | Anqi Luo |
| collection | DOAJ |
| description | Abstract The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemia remain unclear. In diabetic ApoE−/− mice and human umbilical vein endothelial cell (HUVEC) models, mitophagy is enhanced following short‐term and long‐term high‐glucose exposure. Short‐term high‐glucose exposure promotes Parkin‐mediated mitophagy and upregulates mitochondrial fission protein 1 (Fis1) expression, whereas long‐term high‐glucose exposure suppresses Parkin‐mediated mitophagy and downregulates Fis1. With prolonged high‐glucose exposure, Syntaxin 17 (STX17) translocates from the endoplasmic reticulum to the mitochondria, activating STX17‐mediated mitophagy. Silencing STX17 alleviates mitochondrial degradation, decreases reactive oxygen species (ROS) levels, enhances endothelial nitric oxide synthase (eNOS) phosphorylation, and reduces apoptosis. Silencing Fis1 accelerates the switching to STX17‐mediated mitophagy, worsening endothelial dysfunction, whereas Fis1 overexpression prevents this switching, reducing ROS and apoptosis and enhancing eNOS phosphorylation. In summary, these findings suggest that the switching from Parkin‐mediated to STX17‐mediated mitophagy drives vascular endothelial injury following long‐term hyperglycemic exposure, providing valuable insights into therapeutic strategies for diabetic cardiovascular complications. |
| format | Article |
| id | doaj-art-06589aeb445540f6b360b37fc60472d4 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-06589aeb445540f6b360b37fc60472d42025-08-20T02:26:18ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202414960Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular InjuryAnqi Luo0Rui Wang1Jingwen Gong2Shuting Wang3Chuan Yun4Zongcun Chen5Yanan Jiang6Xiaoquan Liu7Haofu Dai8Haochen Liu9Yunsi Zheng10School of Pharmacy China Pharmaceutical University Nanjing 211198 ChinaKey Laboratory of Hainan Trauma and Disaster Rescue Hainan Medical University Haikou 571199 ChinaSchool of Pharmacy Hainan Medical University Haikou 571199 ChinaSchool of Pharmacy Hainan Medical University Haikou 571199 ChinaClinical Research Center for Metabolic Disease The First Affiliated Hospital of Hainan Medical University Haikou 570102 ChinaDepartment of Endocrinology The Second Affiliated Hospital of Hainan Medical University Haikou 570311 ChinaDepartment of Pharmacy The Second Affiliated Hospital of Hainan Medical University Haikou 570311 ChinaSchool of Pharmacy China Pharmaceutical University Nanjing 211198 ChinaHainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine Chinese Academy of Tropical Agriculture Sciences Haikou 571101 ChinaSchool of Pharmacy China Pharmaceutical University Nanjing 211198 ChinaKey Laboratory of Hainan Trauma and Disaster Rescue Hainan Medical University Haikou 571199 ChinaAbstract The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemia remain unclear. In diabetic ApoE−/− mice and human umbilical vein endothelial cell (HUVEC) models, mitophagy is enhanced following short‐term and long‐term high‐glucose exposure. Short‐term high‐glucose exposure promotes Parkin‐mediated mitophagy and upregulates mitochondrial fission protein 1 (Fis1) expression, whereas long‐term high‐glucose exposure suppresses Parkin‐mediated mitophagy and downregulates Fis1. With prolonged high‐glucose exposure, Syntaxin 17 (STX17) translocates from the endoplasmic reticulum to the mitochondria, activating STX17‐mediated mitophagy. Silencing STX17 alleviates mitochondrial degradation, decreases reactive oxygen species (ROS) levels, enhances endothelial nitric oxide synthase (eNOS) phosphorylation, and reduces apoptosis. Silencing Fis1 accelerates the switching to STX17‐mediated mitophagy, worsening endothelial dysfunction, whereas Fis1 overexpression prevents this switching, reducing ROS and apoptosis and enhancing eNOS phosphorylation. In summary, these findings suggest that the switching from Parkin‐mediated to STX17‐mediated mitophagy drives vascular endothelial injury following long‐term hyperglycemic exposure, providing valuable insights into therapeutic strategies for diabetic cardiovascular complications.https://doi.org/10.1002/advs.202414960(diabetesFis1mitophagySyntaxin 17)vascular endothelial injury |
| spellingShingle | Anqi Luo Rui Wang Jingwen Gong Shuting Wang Chuan Yun Zongcun Chen Yanan Jiang Xiaoquan Liu Haofu Dai Haochen Liu Yunsi Zheng Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury Advanced Science (diabetes Fis1 mitophagy Syntaxin 17) vascular endothelial injury |
| title | Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury |
| title_full | Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury |
| title_fullStr | Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury |
| title_full_unstemmed | Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury |
| title_short | Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia‐Induced Vascular Injury |
| title_sort | syntaxin 17 translocation mediated mitophagy switching drives hyperglycemia induced vascular injury |
| topic | (diabetes Fis1 mitophagy Syntaxin 17) vascular endothelial injury |
| url | https://doi.org/10.1002/advs.202414960 |
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