2. Academic Validation
  3. Extracellular Mitochondrial-Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction

Extracellular Mitochondrial-Derived Vesicles Affect the Progression of Diabetic Foot Ulcer by Regulating Oxidative Stress and Mitochondrial Dysfunction

  • Adv Sci (Weinh). 2025 Jan 21:e2407574. doi: 10.1002/advs.202407574.
Huihui Zhang 1 2,  Zi Yan 2 3 4,  Junyou Zhu 5,  Ziyue Li 2 4,  Lianglong Chen 1,  Weihan Zheng 2 4,  Zhenning Dai 6,  Jiaxin Yang 2,  Xinyi Yun 2,  Yilin Wang 2,  Hai Zhou 1,  Ziwei Jiang 1,  Qiuyi Yu 1,  Shiyu Li 3,  Wenhua Huang 2 4,  Lei Yang 1
Affiliations

Affiliations

  • 1 Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 2 Guangdong 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, China.
  • 3 Department of Microbiology and Immunology, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou, 510632, China.
  • 4 Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, 510630, China.
  • 5 Department of Burns, First affiliated hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 6 Department of Stomatology, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou, 510095, China.
PMID: 39835574 DOI: 10.1002/advs.202407574
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.

Keywords

diabetic foot ulcers; extracellular vesicles; mitochondria; mitochondrial‐derived vesicles; oxidative stress.

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