bims-mitrat 2026-09-27 papers

Mol Neurobiol. 2026 Sep 21. pii: 912. [Epub ahead of print]63(1):

Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.

Xing Wei, Fuxian Liu, Jingxi Yao, Peng Feng, Fuchun Xue, Zhenggang Shi.

Mitochondria are essential organelles that maintain neuronal bioenergetics, redox homeostasis, calcium signaling, and immune regulation. Traditionally, mitochondrial dysfunction has been primarily considered as an intracellular event associated with neuronal injury and neurodegeneration. However, accumulating evidence indicates that mitochondria and mitochondrial components can be transferred between cells, forming an intercellular communication network that dynamically regulates tissue homeostasis and disease progression. Intercellular mitochondrial transfer occurs through contact-dependent pathways, mainly mediated by tunneling nanotubes (TNTs), and contact-independent pathways involving mitochondrial extracellular vesicles (MitoEVs), mitochondria-derived extracellular vesicles (MDEVs), and extracellular mitochondria. In the nervous system, these pathways establish functional interactions among neurons, astrocytes, microglia, satellite glial cells, endothelial cells, and stem cells. Transferred functional mitochondria can restore bioenergetic deficits, whereas damaged mitochondria or mitochondrial components may act as danger-associated molecular patterns (DAMPs) to amplify neuroinflammation. Here, we summarize the molecular mechanisms and biological functions of intercellular mitochondrial transfer in the nervous system, emphasizing its dual roles in bioenergetic rescue, mitochondrial quality control, and neuroimmune regulation. Understanding these processes may provide new insights into neurological disease mechanisms and therapeutic strategies targeting mitochondrial communication.

Keywords: Bioenergetics; Intercellular mitochondrial transfer; Mitochondrial extracellular vesicles; Neuroimmune interactions; Neuroinflammation; Tunneling nanotubes

DOI: https://doi.org/10.1007/s12035-026-06224-w

Front Cell Dev Biol. 2026 ;14 1927682

Mitochondrial transfer and transplantation in tendon, ligament, and enthesis repair: current evidence, mechanistic rationale, and regenerative opportunities.

Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Zechen Zhang, Chengjie Wang, Binbin Tang, Xiaolin Shi, Kang Liu.

Tendon, ligament, and enthesis injuries often heal through fibrovascular scar rather than restoration of native matrix organization, mechanical function, and graded interface architecture. Mitochondrial dysfunction has emerged as a recurrent feature of these repair failures, linking impaired bioenergetics, oxidative stress, persistent inflammation, cell death, and defective matrix remodeling. In parallel, mitochondria are increasingly recognized as transferable organelles that can move between cells or be delivered therapeutically as isolated mitochondria, mitochondria-rich extracellular vesicles, or engineered mitochondria-based products. This review examines mitochondrial transfer and transplantation as organelle-level mechanisms and therapeutic strategies in tendon, ligament, rotator cuff muscle, and enthesis-related repair. We define key terminology and characterization requirements for verifying mitochondrial identity, integrity, uptake, and function, and synthesize evidence across disease-relevant repair contexts. Direct preclinical support is most developed in tendinopathy/tendon repair and rotator cuff tear-associated muscle degeneration, whereas evidence in anterior cruciate ligament-related repair remains early, and application to enthesis regeneration or tendon-to-bone healing is still largely hypothesis-driven. Further therapeutic development will depend on defined donor sources, product identity, indication-specific potency, tissue retention, dosing strategies, safety assessment, disease-relevant models, and functional endpoints.

Keywords: enthesis; ligament repair; mitochondrial transfer; mitochondrial transplantation; tendon repair; tendon-to-bone healing

DOI: https://doi.org/10.3389/fcell.2026.1927682

J Transl Med. 2026 Sep 19. pii: 1205. [Epub ahead of print]24(1):

Horizontal mitochondrial transfer and mitochondrial transplantation in skin: protection against UVR-induced ROS damage and enhancement of cell proliferation and wound healing.

BACKGROUND: Skin homeostasis, protection against ultraviolet radiation (UVR), and wound repair depend on coordinated interactions among melanocytes, keratinocytes, and fibroblasts. Horizontal mitochondrial transfer (HMT) is a naturally occurring form of intercellular communication in which mitochondria move between cells and may contribute to stress adaptation, cellular recovery, and tissue resilience. Artificial mitochondrial transfer (AMT), performed in vitro or ex vivo, and mitochondrial transplantation (MT), involving the direct administration of isolated mitochondria in vivo, seek to therapeutically harness these biological mechanisms. However, HMT among resident skin cells and its relationship to mitochondria-based regenerative strategies remain poorly understood.
METHODS: HMT among human melanocytes, keratinocytes, and fibroblasts was evaluated under basal conditions and following UVR exposure. Direct 2D coculture and transwell systems were used to assess predominantly contact-dependent and contact-independent HMT, respectively, using fluorescence microscopy. AMT was performed by delivering isolated mitochondria from human fibroblast, human Wharton's jellymesenchymal stem/stromal cells (WJ-MSCs), or mouse bone marrow MSCs (BM-MSCs) to recipient fibroblasts, followed by assessment of mitochondrial uptake, reactive oxygen species (ROS) production, and cell proliferation. The regenerative effects of locally administered MSC-derived mitochondria were subsequently evaluated in murine and porcine primary-intention wound models: mouse BM-MSC-derived mitochondria were used in murine wounds, whereas human WJ-MSC-derived mitochondria were used in porcine wounds. Outcomes were assessed using histological analysis, the wound healing index (WHI), and, in pigs, spatial quantification of Ki67-positive cells.
RESULTS: HMT from melanocytes to keratinocytes increased significantly after UVR exposure and occurred predominantly under direct coculture conditions, reaching approximately 39%, compared with less than 9% in transwell assays. HMT in the other donor-recipientcombinationsremainedbelow4%.AMTusing human WJ-MSC-derived mitochondria reduced UVR-induced ROS production, while mitochondria derived from both human WJ-MSCs and mouse BM-MSCs significantly increased fibroblast proliferation, although the magnitude of these effects depended on the mitochondrial dose. In murine wounds, locally administered BM-MSC-derived mitochondria enhanced early histological repair and produced effects comparable to those observed after intact BM-MSC administration. In porcine wounds, WJ-MSC-derived mitochondria increased the WHI, improved collagen-containing tissue organization, and enhanced Ki67 positivity within epidermal and dermal regions directly involved in wound repair.
CONCLUSIONS: These findings identify HMT as a cell-type-specific response in the skin, with preferential HMT from melanocytes to keratinocytes that is enhanced by UVR exposure. They also demonstrate that MSC-derived mitochondria can reduce oxidative stress, stimulate fibroblast proliferation, and promote early cutaneous repair after local administration. Together, the results establish a translational link between endogenous mitochondrial exchange and the therapeutic use of AMT and MT, supporting further development of mitochondria-based, cell-free strategies for skin injury and impaired wound healing.

Keywords: Artificial Mitochondrial Transfer (AMT); Artificial Mitochondrial Transfer/Transplant (AMT/T); Fibroblast; Horizontal Mitochondrial Transplant (HMT); Keratinocytes; Melanocytes; Mitochondria; Mitochondrial Transplant (MT); Reactive Oxygen Species (ROS); Regeneration; Repair; Skin; Ultraviolet Radiation (UVR); Wound Healing

DOI: https://doi.org/10.1186/s12967-026-08801-y

Antioxidants (Basel). 2026 Sep 04. pii: 1120. [Epub ahead of print]15(9):

Mitochondrial Transplantation Suppresses mtDNA-cGAS/STING-Mediated Innate Immunity by Enhancing PINK1/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis.

Wenjing Wang, Yuanbo Liu, Jipeng Song, Zouzou Yu, Zixiang Chen, Hu Jiao.

Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach.

Keywords: adipose-derived stem cells; cGAS/STING signaling; fibrosis; innate immunity; keloids; mitochondrial transplantation; mitophagy

DOI: https://doi.org/10.3390/antiox15091120

Front Mol Neurosci. 2026 ;19 1855078

Additive protection of transcranial direct current stimulation and mitochondrial transplantation on ischemic stroke via inducing A2 astrocytes.

Yaomin Guo, En-Ming Kang, Min Li, Taozhi Wang, Zhongqing Sun, Yazhou Wang, Wen Jiang, Jiang Li.

Introduction: Therapeutic options for the acute phase of ischemic stroke remain limited. Transcranial direct current stimulation (tDCS) and mitochondrial transplantation have emerged as promising neuroprotective approaches, but their individual efficacy is variable. We hypothesized that combining these two therapies would produce additive benefits for post-stroke recovery.
Methods: Focal cortical ischemia was induced in mice using photothrombotic technique. Mice were randomly assigned to receive sham treatment, tDCS, mitochondrial transplantation, or combined treatment. Grid-walking, cylinder tests and 2,3,5-triphenyltetrazolium chloride staining were used to assess motor recovery and infarct volume, respectively. Immunofluorescence staining, and western blotting were performed to determine mitochondrial internalization and polarization of astrocytes in vivo and in vitro.
Results: Combining tDCS with mitochondrial transplantation resulted in a significantly greater reduction in infarct volume and improvement in locomotor function compared to either treatment alone. Interestingly, tDCS specifically enhanced the uptake of exogenous mitochondria by astrocytes. This was associated with a significant increase in beneficial A2 astrocytes and decrease in detrimental A1 astrocytes. Mechanistically, the combined treatment led to a marked upregulation of CD38 in astrocytes, suggesting their involvement in the tDCS-facilitated mitochondrial endocytosis. Suppression of CD38 expression by short interfering RNA attenuated astrocyte mitochondrial endocytosis and A2 phenotype induced by tDCS.
Conclusion: Our findings demonstrate that combining tDCS with mitochondrial transplantation conferred superior neuroprotection against ischemic brain damage than either treatment alone, and may represent a promising strategy for ischemic stroke treatment.

Keywords: astrocytes; endocytosis; ischemic stroke; mitochondria; tDCS; transplantation

DOI: https://doi.org/10.3389/fnmol.2026.1855078

Small. 2026 Sep 24. e75883

Surface-Engineered Mitochondrial Extracellular Vesicles for Enhanced Endosomal Escape and Alleviation of Osteoarthritis-Associated Neuropathic Pain.

Zhan Liu, Zeyu Han, Qingwei Wu, Rui Chao, Tianhao Wan, Yangbin Wang, Weifeng Xu, Xuzhuo Chen, Shanyong Zhang.

Mitochondrial transfer has emerged as a promising therapeutic strategy for disease driven by neural and pain-related pathologies. However, inefficient intracellular delivery and severe lysosomal degradation significantly limit its translational potential. Given the critical role of mitochondrial dysfunction in Schwann cells (SCs) and macrophages during neuropathic pain progression in temporomandibular joint arthritis and knee osteoarthritis, this study presents an optimised nanomedicine treatment approach using mitochondria-derived extracellular vesicles (MitoEVs). Here, we isolated functional MitoEVs from SCs for surface modification with a novel micellar material, R8-HDA (yielding R-MitoEVs), to enhance efficient endosomal escape. Our results demonstrate that R-MitoEVs exhibit augmented cellular uptake and enhance evasion of lysosomal degradation, thereby preserving the structural integrity and bioactivity of the transferred mitochondria. Consequently, R-MitoEVs suppressed lipopolysaccharide-induced pro-inflammatory macrophage polarisation and downregulated TNF-α/NF-κB signalling. Concurrently, the R-MitoEV-derived mitochondria restored metabolic homeostasis in SCs by quenching reactive oxygen species and augmenting antioxidant capacity. In vivo evaluations demonstrated the therapeutic efficacy of R-MitoEVs, characterised by enhanced chondrocyte resilience and the significant downregulation of pain-related neuronal markers (TRPV1 and CGRP) and pro-inflammatory mediators. Overall, this surface-engineered R-MitoEVs platform mitigates the biological barriers of mitochondrial delivery, offering a promising therapeutic strategy for mitigating osteoarthritis and its associated neuropathic pain.

Keywords: TRPV1; chondrocyte; downregulation and upregulation; extracellular vesicle; macrophage; microvesicles; mitochondrion; neuropathic pain; osteoarthritis; reactive oxygen species

DOI: https://doi.org/10.1002/smll.75883

Aging Cell. 2026 Oct;25(10): e70720

Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.

Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie.

Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.

Keywords: HIF‐3α‐BNIP3 axis; aging heart; mitochondrial transplantation; mitophagy flux

DOI: https://doi.org/10.1111/acel.70720