Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy
Abstract Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron–sulfur (...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406695 |
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| author | Mengyi Wang Shiwu Zhang Jinwei Tian Fan Yang He Chen Shuzhi Bai Jiaxin Kang Kemiao Pang Jiayi Huang Mingjie Dong Shiyun Dong Zhen Tian Shaohong Fang Huitao Fan Fanghao Lu Bo Yu Shuijie Li Weihua Zhang |
| author_facet | Mengyi Wang Shiwu Zhang Jinwei Tian Fan Yang He Chen Shuzhi Bai Jiaxin Kang Kemiao Pang Jiayi Huang Mingjie Dong Shiyun Dong Zhen Tian Shaohong Fang Huitao Fan Fanghao Lu Bo Yu Shuijie Li Weihua Zhang |
| author_sort | Mengyi Wang |
| collection | DOAJ |
| description | Abstract Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron–sulfur (Fe–S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S‐sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H2S) supplementation restores NFS1 S‐sulfhydration at cysteine 383 residue, thereby enhancing Fe–S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe–S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes. |
| format | Article |
| id | doaj-art-2f2c234c586246c7a35824e308e2ae7b |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2f2c234c586246c7a35824e308e2ae7b2025-08-20T02:47:32ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202406695Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic CardiomyopathyMengyi Wang0Shiwu Zhang1Jinwei Tian2Fan Yang3He Chen4Shuzhi Bai5Jiaxin Kang6Kemiao Pang7Jiayi Huang8Mingjie Dong9Shiyun Dong10Zhen Tian11Shaohong Fang12Huitao Fan13Fanghao Lu14Bo Yu15Shuijie Li16Weihua Zhang17Department of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaDepartment of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaDepartment of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaDepartment of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaDepartment of Forensic Medicine Harbin Medical University Harbin 150000 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaCollege of Bioinformatics Science and Technology Harbin Medical University Harbin 150000 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaDepartment of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaDepartment of Critical Care Medicine The First Affiliated Hospital of Harbin Medical University Harbin 150001 ChinaDepartment of Pathophysiology Harbin Medical University Harbin 150000 ChinaDepartment of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaState Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD) Department of Biopharmaceutical Sciences College of Pharmacy Harbin Medical University Harbin 150000 ChinaDepartment of Cardiology Second Affiliated Hospital of Harbin Medical University No. 246 Xuefu ROAD Harbin 150086 ChinaAbstract Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron–sulfur (Fe–S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S‐sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H2S) supplementation restores NFS1 S‐sulfhydration at cysteine 383 residue, thereby enhancing Fe–S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe–S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes.https://doi.org/10.1002/advs.202406695cysteine desulfurase (NFS1)diabetic cardiomyopathy (DCM)hydrogen sulfide (H2S)iron–sulfur (Fe–S) clusterPARthanatos |
| spellingShingle | Mengyi Wang Shiwu Zhang Jinwei Tian Fan Yang He Chen Shuzhi Bai Jiaxin Kang Kemiao Pang Jiayi Huang Mingjie Dong Shiyun Dong Zhen Tian Shaohong Fang Huitao Fan Fanghao Lu Bo Yu Shuijie Li Weihua Zhang Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy Advanced Science cysteine desulfurase (NFS1) diabetic cardiomyopathy (DCM) hydrogen sulfide (H2S) iron–sulfur (Fe–S) cluster PARthanatos |
| title | Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy |
| title_full | Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy |
| title_fullStr | Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy |
| title_full_unstemmed | Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy |
| title_short | Impaired Iron–Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy |
| title_sort | impaired iron sulfur cluster synthesis induces mitochondrial parthanatos in diabetic cardiomyopathy |
| topic | cysteine desulfurase (NFS1) diabetic cardiomyopathy (DCM) hydrogen sulfide (H2S) iron–sulfur (Fe–S) cluster PARthanatos |
| url | https://doi.org/10.1002/advs.202406695 |
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