bims-mitrat 2025-06-08 papers

ACS Nano. 2025 May 31.

Mesenchymal Stem Cell-Derived Mitochondrial Transfer Promotes Tip Cell Phenotype via Glutathione Metabolic Reprogramming in Stroke Mice.

Qiao Zhang, Jiaxin Huang, Xi Chen, Lang Li, Lin Chen, Xin Zhou, Xingli Zhao, Min Liu, Wenyan Zhao, Juan Yan, Yueying Wang, Yang Su, Yong Liu, Shangcheng Xu, Wen Zeng.

Angiogenesis is crucial to improving neurovascular remodeling poststroke. Therein, the transformation of endothelial cells (ECs) to tip cells is essential in initiating angiogenesis. Mitochondrial damage in ECs poststroke and associated metabolic disorder are key factors repressing angiogenesis, but the mechanisms are unknown. Here, we designed an Arg-Gly-Asp peptide (RGD)-modified, mitochondria-enriched, and extracellular vesicle mimetics (mitoEVMs) platform for mitochondrial transfer. RGD mediated the mesenchymal stem cell-derived mitochondria transfer to ECs around the lesion targetedly. We found MSC-derived mitochondria promoted tip cell transition and further stimulated angiogenesis after stroke, alleviated brain atrophy, and improved functional rehabilitation. We noticed mitochondrial transfer rescued mitochondrial function in ECs and reprogrammed glutathione metabolism to activate the mTORC1 pathway, upregulated the expression of p4E-BP1 and VEGFR2, and ultimately facilitated tip cell transition. Our work elucidates the mechanism of MSC-derived mitochondrial transfer in poststroke treatment and proposes a potential approach for rehabilitation after stroke.

Keywords: angiogenesis; glutathione; mitochondria transfer; stroke; tip cell

DOI: https://doi.org/10.1021/acsnano.4c15759

Synapse. 2025 Jul;79(4): e70022

Efficacy of Mitochondrial Transfer in Healing Toxin-Induced Damage to Neuromuscular Junction, an Empirical Study.

Michael R Deschenes, Max Rackley, Sophie Fernandez, Megan Heidebrecht, Kate Hamilton, Hector G Paez, Christopher R Paez, Stephen E Alway.

Neuromuscular diseases and damage affect many people of all ages and are responsible for an exorbitant medical cost, more than $200 million annually. Accordingly, finding an appropriate model to investigate potential curative interventions is necessary. One currently used involves the application of toxic agents on skeletal muscle followed by mitochondrial transplant therapy. A question regarding this model is whether such toxins impact not only muscle tissue but also the neuromuscular junctions (NMJs) responsible for exciting the muscle tissue. This question was addressed here by forming four experimental groups of C57BL/six mice (10-14 per group) that were 8-12 weeks of age: 1) controls whose muscles had not been injured or treated, 2) muscles taken from mice that were injured and then treated with mitochondrial supplement, 3) muscles that had not been injured but were still treated with mitochondria, and 4) muscles that were injured and received no mitochondrial treatment. Several pre- and postsynaptic features of NMJs were subject to immunofluorescent staining procedures before having morphological features assessed with confocal microscopy. Results revealed that only postsynaptic acetylcholine (ACh) receptors showed any significant (p < 0.05) between-group differences, including decreased area size and perimeter length around ACh receptor clusters in injured NMJs. However, presynaptic nerve terminal branching was not different (p > 0.05) among treatment groups, and structural features were not different between groups with the exception of dispersion of postsynaptic receptors. Overall, these results suggest that skeletal muscles damaged with toxin accurately mimic what occurs during toxin-induced damage and post-injury recovery and can be used as a faithful model of occurrences during damage to NMJs as a result of muscle damage along with recovery from that insult.

Keywords: bungarotoxin; confocal; myofiber; synapse

DOI: https://doi.org/10.1002/syn.70022

J Transl Med. 2025 Jun 03. 23(1): 624

A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation.

Yehree Kim, Yujin Kim, Bong Jik Kim, Shin-Hye Yu, Jin Hee Han, Minyoung Kim, Nayoung Yi, Seo-Eun Lee, Ju Ang Kim, Kyuboem Han, Chun-Hyung Kim, Young Cheol Kang, Byung Yoon Choi.

BACKGROUND: A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD).
METHODS: Exome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea. Mitochondrial function was evaluated by measuring intracellular ATP, ROS and mitochondrial membrane potential in control and patient-derived lymphoblastoid cells (LCLs) before and after the administration of mitochondria isolated from human umbilical cord mesenchymal stem cells (UC-MSCs).
RESULTS: ANSD observed in our study is characterized by initial inner hair cell damage, followed by accelerated degeneration of cochlear outer hair cells. Functional studies of patient-derived LCLs revealed mitochondrial dysfunction, evidenced by increased ROS, reduced ATP levels, and decreased mitochondrial membrane potential compared with normal LCLs. Further, these cells demonstrated heightened sensitivity to cisplatin-induced apoptosis, as indicated by the increased proapoptotic gene expression. Notably, the administration of mitochondria isolated from umbilical cord mesenchymal stem cells significantly restored mitochondrial dysfunction and alleviated cisplatin-induced cytotoxicity in the patient-derived cells.
CONCLUSIONS: These results indicate BCAP31 dysfunction as a potential cause of transient ANSD, progressing to sensorineural hearing loss through mitochondrial impairment. Furthermore, they highlighted the therapeutic potential of allogenic mitochondrial transplantation as a novel strategy for treating hearing loss with an underlying component of mitochondrial dysfunction. This study contributes to the understanding of BCAP31's role in auditory neuropathy and mitochondrial health.

Keywords: Apoptosis; BAP31/BCAP31; Hearing loss; Mitochondria; Transplantation

DOI: https://doi.org/10.1186/s12967-025-06610-3