bims-mitrat 2025-08-17 papers

Sci Rep. 2025 Aug 09. 15(1): 29167

Therapeutic potential of human mesenchymal stromal cell-derived mitochondria in a rat model of surgical digestive fistula.

Antoine Mariani, Augustin Guichard, Anna C Sebbagh, André Cronemberger Andrade, Zahra Al Amir Dache, Christopher Ribes, Dmitry Ayollo, Mehdi Karoui, Gregory Lavieu, Florence Gazeau, Amanda K A Silva, Gabriel Rahmi, Sabah Mozafari.

Mitochondria are central to cellular energy metabolism and play a critical role in tissue regeneration. Mitochondrial dysfunction contributes to a range of degenerative conditions and impaired wound healing, driving increasing interest in mitochondrial transplantation as a novel therapeutic strategy. Gastrointestinal wound healing is particularly susceptible to failure, with complications such as post-surgical fistula formation commonly occurring after procedures like sleeve gastrectomy. Mitochondria derived from human mesenchymal stromal/stem cells (hMSCs) have shown promise in restoring tissue bioenergetics and promoting repair across various disease models. In this study, we evaluated the therapeutic potential of hMSC-derived mitochondria as a nano-biotherapy for gastrointestinal wound healing using a rat model of post-operative fistula. Structurally intact mitochondria were isolated from hMSCs and either applied to human colonic epithelial cells (HCEC-1CT) in vitro or transplanted locally into fistula-bearing rats. Mitochondrial treatment led to a dose-dependent increase in cellular metabolic activity, intracellular ATP levels, and mitochondrial uptake by recipient cells. In vivo, mitochondrial transplantation significantly accelerated fistula closure and tissue regeneration compared to controls. These findings underscore the translational promise of mitochondria-based, cell-free therapies and lay the groundwork for future regenerative strategies targeting gastrointestinal wound repair.

Keywords: Biotherapy; Human mesenchymal stromal cells (hMSCs); Mitochondria transplantation; Post-surgical fistula; Wound healing, regenerative medicine

DOI: https://doi.org/10.1038/s41598-025-13887-3

Bioact Mater. 2025 Nov;53 773-788

Autophagic-active nanosystem for senile bone regeneration by in-situ mitochondrial biogenesis and intercellular transfer.

Meihua Zhang, Xiaoqing Sun, Ming Lu, Xingyou Wang, Shuyao Liu, Xiaoqin Hu, Jing He, Bin Luo, Yao Wu.

Natural intercellular mitochondrial transfer has been recognized as a pivotal mechanism in the treatment of various diseases. Bone marrow mesenchymal stem cells (BMSCs), owing to their low bioenergetic demands and inherent homing capacity, are considered highly promising mitochondrial donor cells. However, this strategy is limited in senile osteoporosis (SOP) because large amounts of ROS produced by mitochondrial oxidative stress in senescent BMSCs (S-BMSCs) impairs their viability and function. Here, we report that in-situ treatment of senescent bone marrow-derived macrophages (S-BMDMs) with a cerium-based nanosystem (CNS) composed of antioxidant and energy-active units, which exhibits superior autophagy-activating capability, effectively restores the viability and osteogenic function of S-BMSCs by promoting mitochondrial biogenesis and transfer. Transcriptomic profiling revealed that the SIRT1-PGC-1α axis, significantly associated with autophagy activation, drives mitochondrial biogenesis in S-BMDMs. The efficient intercellular mitochondrial transfer ameliorates the senescent bone microenvironment, rescues S-BMSCs functionality, and enhances bone formation. In conclusion, the autophagy-activating CNS, by effectively rejuvenating S-BMDMs and promoting mitochondrial biogenesis and transfer, provides an innovative therapeutic strategy for SOP-associated bone regeneration.

Keywords: Autophagy activation; Cerium-based nanosystem; Mitochondrial biogenesis; Mitochondrial transfer; Senile osteoporosis

DOI: https://doi.org/10.1016/j.bioactmat.2025.07.034

J Leukoc Biol. 2025 Aug 11. pii: qiaf119. [Epub ahead of print]

Platelet-Derived Microvesicles Modulate the Bioenergetic and Inflammatory Phenotype of Human Polymorphonuclear Leukocytes.

Marie-France N Soucy, Mathieu P A Hébert, Jérémie A Doiron, David A Barnett, Simon G Lamarre, Etienne Hebert-Chatelain, Luc H Boudreau.

Platelets release microvesicles (PMVs) into the extracellular milieu upon activation. PMVs retain various platelet components, including functional mitochondria, and actively participate in intercellular communication with immune cells such as polymorphonuclear leukocytes (PMN). PMVs have been known to modulate the inflammatory response of PMN under normal physiological condition. Despite growing interest in the transfer of biological material between immune cells, the mitochondrial content shuttling from PMVs to PMN and the resulting effects have remained unclear. Using freshly isolated PMVs from healthy and consenting donors, we demonstrate that PMVs modulate both the bioenergetic and the inflammatory phenotype of the recipient immune cell. We first confirmed the mitochondrial content transfer, and then measured cell viability, mitochondrial respiration, and ATP production. Platelet-derived mitochondria were found associated with PMN, consequently decreasing caspase-3 activity. PMVs increased mitochondrial activity and ATP levels in the recipient cell. Incubation of PMN with PMVs containing non-functional mitochondria did not affect respiration and caspase-3 activity. This demonstrates that functional and active mitochondria are required for the PMVs to modulate the bioenergenetic phenotype of human polymorphonuclear leukocytes. Finally, we detected the transfer of active 12-lipoxygenase and of cyclooxygenase-1 in the recipient cells, enzymes found specifically in PMVs, and an increase in the production of their respective inflammatory products. These findings suggest that platelet-derived mitochondria play a key role in enhancing the survival and inflammatory function of PMN in inflammatory conditions.

Keywords: eicosanoids; mitoMPs; mitochondria; platelet microvesicles; sterile inflammation

DOI: https://doi.org/10.1093/jleuko/qiaf119

J Nanobiotechnology. 2025 Aug 11. 23(1): 559

Dynamic three-dimensional culture enhances tunneling nanotubes-mediated mitochondrial transfer in mesenchymal stromal cells to accelerate wound healing.

Lin Ma, Xiaoxue Yang, Xiaoyao Huang, Hao Guo, Zihan Li, Siyuan Fan, Han Qin, Fanhui Meng, Peisheng Liu, Xinyu Wang, Meiling Wu, Kun Xuan, Anqi Liu.

Mesenchymal stromal cells (MSCs) have shown promise in treating various diseases, and optimizing their therapeutic potential is a crucial objective in MSCs-based clinical applications. The microenvironment, particularly three-dimensional (3D) culture systems, plays a pivotal role in regulating the fate determination and enhancing the therapeutic potential of MSCs. Currently, the mechanisms governing the interactions between MSCs cultured in a dynamic 3D system and host recipient cells remain incompletely understood. MSCs transfer mitochondria to influence the fate of recipient cells, with tunneling nanotubes (TNTs) being the primary method. However, whether MSCs cultured under dynamic 3D conditions transfer mitochondria via TNTs to exert therapeutic effects remains to be elucidated. This study developed a dynamic 3D culture system for stem cells from human exfoliated deciduous teeth (SHED), a type of MSCs, utilizing gelatin microcryogel microcarriers and stirred tank bioreactor. A mouse model of full-thickness skin defects was employed to validate the enhanced therapeutic efficacy of SHED cultured under dynamic 3D conditions. Co-culture experiments with SHED and endothelial cells demonstrated that the dynamic 3D culture conditions empower the MSCs to transfer mitochondria via TNTs, thereby promoting angiogenesis. This research provides novel insights into the mechanisms underlying wound healing acceleration by SHED cultured under dynamic 3D conditions and offers a new strategy for developing MSCs transplantation applications.

Keywords: Cell therapy; Mesenchymal stromal cells; Mitochondrial transfer; Three-dimensional culture; Tunneling nanotubes; Wound healing

DOI: https://doi.org/10.1186/s12951-025-03655-w

Cell Mol Neurobiol. 2025 Aug 14. 45(1): 79

Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage.

Tong Shang, Binglin Kuang, Lei Zheng, Baiwen Zhang, Xueting Liu, Yaxin Shang, Jia Zheng, Baochun Luo, Wei Zou.

Mitochondrial dysfunction has been identified as a key factor in the pathophysiological changes associated with intracerebral hemorrhage (ICH). As the core of intracellular energy metabolism, mitochondrial homeostasis is highly dependent on the precise regulation of its mitochondrial quality control (MtQC) system. After ICH, dysfunctional mitochondria lead to impaired oxidative phosphorylation and cellular bioenergetic stress, inducing oxidative stress, inflammatory responses, and programmed cell death, further exacerbating cellular damage. To counteract this injury, cells activate a series of MtQC mechanisms for compensatory repair, including mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and intercellular mitochondrial transfer. These stringent mechanisms help maintain the mitochondrial network, restore the integrity of mitochondrial structural and functional integrity, improve neural function, and mitigate brain injury. In this review, we discuss key evidence regarding the role of mitochondrial dysfunction in ICH, focusing on the MtQC mechanisms involved in ICH. We also summarize potential therapeutic strategies targeting MtQC to intervene in ICH, providing valuable insights for clinical applications.

Keywords: Intercellular mitochondrial transfer; Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial quality control; Mitophagy

DOI: https://doi.org/10.1007/s10571-025-01599-1

Cells. 2025 Jul 25. pii: 1148. [Epub ahead of print]14(15):

Intranasal Mitochondrial Transplantation Restores Mitochondrial Function and Modulates Glial-Neuronal Interactions in a Genetic Parkinson's Disease Model of UQCRC1 Mutation.

Jui-Chih Chang, Chin-Hsien Lin, Cheng-Yi Yeh, Mei-Fang Cheng, Yi-Chieh Chen, Chi-Han Wu, Hui-Ju Chang, Chin-San Liu.

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson's disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation.

Keywords: Parkinson’s disease; UQCRC1 mutation (p.Tyr314Ser) knock-in mice; cyclosporine A; glial modulation; inflammatory cytokines; intranasal delivery; mitochondrial function; mitochondrial transplantation; neuroprotection; striatal astrocytes; striatal oligodendrocytes

DOI: https://doi.org/10.3390/cells14151148