Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction
Abstract Diabetic foot ulcer (DFU) is a common and severe complication of diabetes mellitus, the etiology of which remains insufficiently understood, particularly regarding the involvement of extracellular vesicles (EVs). In this study, nanoflow cytometry to detect EVs in DFU skin tissues is used an...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407574 |
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| author | Huihui Zhang Zi Yan Junyou Zhu Ziyue Li Lianglong Chen Weihan Zheng Zhenning Dai Jiaxin Yang Xinyi Yun Yilin Wang Hai Zhou Ziwei Jiang Qiuyi Yu Shiyu Li Wenhua Huang Lei Yang |
| author_facet | Huihui Zhang Zi Yan Junyou Zhu Ziyue Li Lianglong Chen Weihan Zheng Zhenning Dai Jiaxin Yang Xinyi Yun Yilin Wang Hai Zhou Ziwei Jiang Qiuyi Yu Shiyu Li Wenhua Huang Lei Yang |
| author_sort | Huihui Zhang |
| collection | DOAJ |
| description | Abstract Diabetic foot ulcer (DFU) is a common and severe complication of diabetes mellitus, the etiology of which remains insufficiently understood, particularly regarding the involvement of extracellular vesicles (EVs). In this study, nanoflow cytometry to detect EVs in DFU skin tissues is used and found a significant increase in the Translocase of Outer Mitochondrial Membrane 20 (TOM20)+ mitochondrial‐derived vesicles (MDVs). The role of MDVs in DFU is yet to be reported. Using single‐cell datasets, it is discovered that the increase in MDVs may be regulated by Sorting Nexin 9 (SNX9). In vitro experiments revealed that MDVs secreted by fibroblasts cultured in high glucose medium exhibited similar composition and protein enrichment results to those in DFU tissues, suggesting their potential as an ideal in vitro surrogate. These MDVs promoted apoptosis and intracellular oxidative stress, disrupted mitochondrial structure, and reduced aerobic metabolism in target cells. In vivo experiments also showed that MDV drops hindered wound healing in diabetic mice; however, this effect is rescued by SNX9 inhibitors, restoring mitochondrial dynamics and balance. Under high glucose conditions, MDVs significantly upregulated oxidative stress levels and induced mitochondrial dysfunction. This study proposes targeting MDVs as a potential therapeutic strategy for DFU. |
| format | Article |
| id | doaj-art-8d31cc2529124051a7da5e86acf1112b |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-8d31cc2529124051a7da5e86acf1112b2025-08-20T02:23:12ZengWileyAdvanced Science2198-38442025-03-011210n/an/a10.1002/advs.202407574Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial DysfunctionHuihui Zhang0Zi Yan1Junyou Zhu2Ziyue Li3Lianglong Chen4Weihan Zheng5Zhenning Dai6Jiaxin Yang7Xinyi Yun8Yilin Wang9Hai Zhou10Ziwei Jiang11Qiuyi Yu12Shiyu Li13Wenhua Huang14Lei Yang15Department of Burns Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaDepartment of Burns First affiliated hospital Sun Yat‐sen University Guangzhou 510080 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaDepartment of Burns Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaDepartment of Stomatology Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine Guangdong Second Traditional Chinese Medicine Hospital Guangzhou 510095 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaDepartment of Burns Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Burns Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Burns Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Microbiology and Immunology College of Basic Medicine and Public Hygiene Jinan University Guangzhou 510632 ChinaGuangdong Engineering Research Center for Translation of Medical 3D Printing Application Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics National Key Discipline of Human Anatomy School of Basic Medical Sciences Southern Medical University Guangzhou 510515 ChinaDepartment of Burns Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaAbstract Diabetic foot ulcer (DFU) is a common and severe complication of diabetes mellitus, the etiology of which remains insufficiently understood, particularly regarding the involvement of extracellular vesicles (EVs). In this study, nanoflow cytometry to detect EVs in DFU skin tissues is used and found a significant increase in the Translocase of Outer Mitochondrial Membrane 20 (TOM20)+ mitochondrial‐derived vesicles (MDVs). The role of MDVs in DFU is yet to be reported. Using single‐cell datasets, it is discovered that the increase in MDVs may be regulated by Sorting Nexin 9 (SNX9). In vitro experiments revealed that MDVs secreted by fibroblasts cultured in high glucose medium exhibited similar composition and protein enrichment results to those in DFU tissues, suggesting their potential as an ideal in vitro surrogate. These MDVs promoted apoptosis and intracellular oxidative stress, disrupted mitochondrial structure, and reduced aerobic metabolism in target cells. In vivo experiments also showed that MDV drops hindered wound healing in diabetic mice; however, this effect is rescued by SNX9 inhibitors, restoring mitochondrial dynamics and balance. Under high glucose conditions, MDVs significantly upregulated oxidative stress levels and induced mitochondrial dysfunction. This study proposes targeting MDVs as a potential therapeutic strategy for DFU.https://doi.org/10.1002/advs.202407574diabetic foot ulcersextracellular vesiclesmitochondriamitochondrial‐derived vesiclesoxidative stress |
| spellingShingle | Huihui Zhang Zi Yan Junyou Zhu Ziyue Li Lianglong Chen Weihan Zheng Zhenning Dai Jiaxin Yang Xinyi Yun Yilin Wang Hai Zhou Ziwei Jiang Qiuyi Yu Shiyu Li Wenhua Huang Lei Yang Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction Advanced Science diabetic foot ulcers extracellular vesicles mitochondria mitochondrial‐derived vesicles oxidative stress |
| title | Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction |
| title_full | Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction |
| title_fullStr | Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction |
| title_full_unstemmed | Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction |
| title_short | Extracellular Mitochondrial‐Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction |
| title_sort | extracellular mitochondrial derived vesicles affect the progression of diabetic foot ulcer by regulating oxidative stress and mitochondrial dysfunction |
| topic | diabetic foot ulcers extracellular vesicles mitochondria mitochondrial‐derived vesicles oxidative stress |
| url | https://doi.org/10.1002/advs.202407574 |
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