Impaired Mitochondria-Derived Microvesicle Transfer from Schwann Cells Drives Axonal Dysfunction in Diabetic Neuropathy
Recommended Citation
Liu X, Chopp M, Wang L, Zhang Y, Zhang Z. Impaired Mitochondria-Derived Microvesicle Transfer from Schwann Cells Drives Axonal Dysfunction in Diabetic Neuropathy. J Extracell Vesicles 2026; 15.
Document Type
Conference Proceeding
Publication Date
4-23-2026
Publication Title
J Extracell Vesicles
Keywords
adenosine triphosphate, argonaute 2 protein, glucose, inflammasome, messenger RNA, microRNA, mitochondrial protein, nanoparticle, nucleotide binding oligomerization domain like receptor, nystatin plus triamcinolone acetonide, reactive oxygen metabolite, RNA induced silencing complex, streptozocin, animal cell, axon, conditioned medium, conference abstract, controlled study, diabetic neuropathy, down regulation, etiology, exosome, flow cytometry, homeostasis, hyperglycemia, immunoblotting, lipid diet, membrane microparticle, microfluidic device, mitochondrial biogenesis, mitochondrial membrane potential, mitochondrion, mouse, nervous tissue, nonhuman, pathogenesis, Schwann cell, sciatic nerve, spinal ganglion, streptozotocin-induced diabetes mellitus, transmission electron microscopy, ultracentrifugation
Abstract
Introduction: Mitochondrial-derived microvesicles (MDVs) enriched with mitochondrial components are emerging as important mediators of intercellular communication, particularly in tissues with high metabolic demands. Schwann cells (SCs) play a vital role in supporting metabolic homeostasis and axonal function. Mitochondrial dysfunction in SCs contributes to the pathogenesis of diabetic peripheral neuropathy (DPN). However, the specific role of SC-derived MDVs (SC-MDVs) in DPN remains elusive. Methods: SC-MDVs and SC-exosomes were isolated from SC-conditioned media via ultracentrifugation and characterized with nanoparticle tracking analysis (NTA), transmission electron microscopy, and immunoblotting. Mitochondrial function within SC-MDVs was assessed by measuring mitochondrial membrane potential (ΔΨm), ATP, and reactive oxygen species (ROS) levels. Primary DRG neurons were cultured in a microfluidic device. Results: NTA showed that the size of SC-MDVs (200-400 nm) was larger than the size of exosomes (30-150 nm). Flow cytometry analysis revealed that SC-MDVs were enriched with mitochondrial proteins and functional mitochondria. Compared to SC-MDVs from SCs cultured under normal glucose level, SC-MDVs isolated from high glucose (HG, 25 mM) exhibited a 50% reduction in mitochondrial biogenesis protein and loss of ΔΨm (p< 0.01), 40% decrease in ATP production (p< 0.01), and 2.1-fold increased ROS content (p< 0.001). Argonaute 2 (Ago2), a core component of RNA-induced silencing complex, regulates the loading of miRNAs into EVs, enabling repression of target mRNAs in recipient cells. Notably, MDVs isolated from the sera of diabetic patients and from high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice exhibited a 60–70% reduction in Ago2 expression. Furthermore, treatment of DRG neurons with dysfunctional MDVs derived from SC-specific Ago2-deficient sciatic nerve tissues resulted in a marked suppression of axonal growth (p < 0.01). In contrast, administration of naïve SC-derived MDVs restored axonal mitochondrial function, increased ATP levels by 2.5-fold (p < 0.01), and reduced HG-induced activation of the NLRP3 (NOD-like receptor protein 3) inflammasome by 55%, as assessed by immunoblotting in DRG neurons under HG conditions, suggesting that downregulation of Ago2 may disrupt the function of SC-MDVs. Summary/Conclusion: Our results show that SC-MDVs function as critical mediators of SC-axon metabolic coupling, and hyperglycemia-induced SC-MDVs could contribute to DPN pathogenesis.
Volume
15
