bims-mitrat 2025-11-16 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–11–16
eight papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.
Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
Unlocking extracellular mitochondria from bench to clinical application in stroke.
Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.
Transplantation of mesenchymal stromal cell-derived mitochondria alleviates endothelial dysfunction in pre-clinical models of acute respiratory distress syndrome.
Mitochondrial cargo quality determines the paracrine effects of extracellular vesicles derived from vascular endothelial cells.
Hypoxia-preconditioning human bone marrow-derived mesenchymal stem cells induce high-quality mitochondrial transfer through gap junctions to alleviate ischemia-reperfusion injury in liver graft.
Platelets facilitate fat grafting by mitochondrial transfer and reducing oxidative stress in adipose-derived stem cells.

Mitochondrion. 2025 Nov 11. pii: S1567-7249(25)00094-7. [Epub ahead of print]86 102097

Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.

Tuğba Varlik, Didem Algan, Öner Sönmez, Keshav K Singh, Öner Ülger, Gökhan Burçin Kubat, Jørgen Koch, Zeki Yilmaz.

  Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction has been identified as a key factor in the progression of cardiomyocyte apoptosis. We investigated whether the transplantation of healthy mitochondria improves cardiac function by enhancing the contractile function of myocytes. A 6-year-old dog with cardiomyopathy received platelet-derived, viable mitochondria from a healthy donor as adjunctive therapy alongside standard medical management. Mitochondria were isolated from platelets and administered as a single intravenous bolus at a dose of 81,125 μg/mL. This procedure was carried out under continuous ECG and vital signs monitoring. Ventricular systolic function was assessed at multiple intervals using conventional echocardiography and two-dimensional speckle tracking imaging. Our study revealed notable improvement in systolic performance as early as two hours post-transplantation of mitochondria, with enhanced contractility sustained up to 24 h. These studies suggest mitochondrial transplantation may offer a promising intervention or adjunct to conventional treatments for cardiac dysfunction. This report presents the first documented case of intravenous mitochondrial transplantation in canine DCM.

Keywords:  Dilated cardiomyopathy; Mitochondrial transplantation; Speckle tracking echocardiography; Systolic myocardial dysfunction; Translational medicine

DOI:  https://doi.org/10.1016/j.mito.2025.102097
Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):

Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.

Margherita Zamberlan, Martina Semenzato.

  Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.

Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes

DOI:  https://doi.org/10.3390/ijms262110581
Stem Cells Transl Med. 2025 Nov 14. pii: szaf060. [Epub ahead of print]14(11):

Unlocking extracellular mitochondria from bench to clinical application in stroke.

Gen Hamanaka, Dong-Bin Back, Ji-Hyun Park, Shin Ishikane, Kazuhide Hayakawa.

  Within the central nervous system (CNS), mitochondria serve as vital energy sources for neurons, glial cells, and vascular functions, maintaining intracellular metabolic balance. Recent studies involving cellular models, rodents, and humans reveal that metabolically active mitochondria can be released into the extracellular space, playing roles in intercellular communication within the CNS. When taken up by neurons, these extracellular mitochondria may provide neuroprotective effects. Conversely, damaged mitochondria and their released components during severe tissue injury or inflammation can contribute to neurodegenerative processes. Thus, mitochondria secreted under pathological conditions in the CNS hold promise as biomarkers indicative of recovery. Additionally, transplantation of external mitochondria shows potential as a therapeutic approach for various CNS disorders. This mini review focuses on recent advances in the transfer of mitochondria between cells, the use of extracellular mitochondria as biomarkers, and the prospects of mitochondria transplantation from experimental research to clinical application, particularly in diseases like stroke.

Keywords:  biomarkers; central nervous system; extracellular mitochondria; mitochondria transplantation; mitochondrial modification; stroke

DOI:  https://doi.org/10.1093/stcltm/szaf060
Mitochondrion. 2025 Nov 12. pii: S1567-7249(25)00095-9. [Epub ahead of print] 102098

Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.

Melody Toosky, Arash Kheradvar.

  Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia-reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, conflicting reports exist regarding whether mitochondria can survive exposure to the calcium-rich extracellular environment, such as the bloodstream, prior to cellular uptake. Resolving this question is essential for advancing the therapeutic use of mitochondria in clinical settings. Isolated mitochondria from L6 rat skeletal muscle cells were incubated with physiologic (1.3  mM), sub-physiologic (0.65  mM), and supraphysiologic (2.6  mM) concentrations of calcium. Mitochondrial membrane potential was assessed using MitoTracker™ Red FM fluorescence, and structural integrity was evaluated using impedance-based Coulter counter analysis over a 12-hour time course. Mitochondria exposed to 1.3  mM calcium retained 90-95 % membrane potential by 12 h, while 2.6  mM calcium caused progressive loss of function and integrity, approaching levels seen in freeze-thawed controls. Coulter counter measurements revealed more extensive mitochondrial loss across all calcium-treated groups than fluorescence assays alone, suggesting that dye-based methods may underestimate structural damage. Nonetheless, a substantial proportion of mitochondria remained both structurally and functionally intact at physiologically relevant calcium levels. These findings demonstrate that a substantial number of mitochondria can retain membrane potential and structural integrity after exposure to extracellular calcium concentrations approximating those found in blood. This supports the feasibility of intracoronary mitochondrial transplantation and underscores the need for further in vivo studies to optimize survival and efficacy of mitochondria delivered in calcium-rich environments.

Keywords:  Calcium overload; Cardioprotection; Extracellular mitochondria; Intracoronary Delivery; Ischemia-reperfusion injury; Mitochondrial membrane potential; Mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.mito.2025.102098
Stem Cells Transl Med. 2025 Nov 14. pii: szaf053. [Epub ahead of print]14(11):

Transplantation of mesenchymal stromal cell-derived mitochondria alleviates endothelial dysfunction in pre-clinical models of acute respiratory distress syndrome.

Dayene de Assis Fernandes Caldeira, Johnatas Dutra Silva, Monique Martins Melo, Rodrigo Gonzaga Veras, Daniel F McAuley, Patricia Rieken Macedo Rocco, Pedro Leme Silva, Fernanda Ferreira Cruz, Anna Krasnodembskaya.

   BACKGROUND: Pulmonary endothelial dysfunction with increased capillary permeability is a key aspect in the pathogenesis of acute respiratory distress syndrome (ARDS). It has been demonstrated that mesenchymal stromal cells (MSC) can modulate host cells through mitochondrial transfer. Although mitochondrial transplantation is a promising treatment strategy for conditions underpinned by mitochondrial dysfunction, its therapeutic potential in ARDS has not been sufficiently investigated. Herein, we tested the potential of MSC mitochondrial transplantation to restore functionality of the pulmonary endothelium in pre-clinical models of ARDS.
METHODS: Mitochondria (mt) derived from human bone-marrow MSC were isolated and immediately used for transplantation to primary human pulmonary microvascular endothelial cells (HPMEC) in the presence of Escherichia coli lipopolysaccharide (LPS) or plasma samples from ARDS patients classified into hypo- and hyper-inflammatory phenotypes. Mitochondrial function, inflammatory status, and barrier integrity of HPMEC were assessed at 24 h. LPS- challenged mice were treated with MSC-mt intravenously, and the severity of lung injury and inflammatory response were evaluated.
RESULTS: Exposure to LPS or ARDS plasma induced endothelial hyperpermeability associated with mitochondrial dysfunction. MSC-mt were readily internalized by HPMEC without cytotoxicity or inflammatory response, mitigating mitochondrial dysfunction and restoring barrier integrity. In vivo, administration of MSC-mt alleviated lung injury, reduced inflammatory cell infiltration in the alveoli and increased VE-cadherin mRNA levels in the lung tissue, indicating restoration of the alveolar-capillary barrier integrity.
CONCLUSION: This study demonstrated MSC mitochondrial transplantation as a promising therapeutic approach for treatment of endothelial dysfunction in the context of acute inflammation. Further exploration of mitochondrial transplantation in ARDS is warranted.

Keywords:  acute respiratory distress syndrome; mesenchymal stromal cells; mitochondrial dysfunction; mitochondrial transplantation; pulmonary endothelial barrier

DOI:  https://doi.org/10.1093/stcltm/szaf053
Biomed Pharmacother. 2025 Nov 13. pii: S0753-3322(25)00945-X. [Epub ahead of print]193 118751

Mitochondrial cargo quality determines the paracrine effects of extracellular vesicles derived from vascular endothelial cells.

Zahid A Manzar, Lucas J Davis, Karl F Swanson, Erik Muñoz, Hazel H Szeto, Hans Minderman, B Rita Alevriadou.

  Cell-derived extracellular vesicles (EV) are mediators of intercellular communication with increased circulating levels of endothelial cell-derived EV (EC-EV) reported in cardiovascular diseases (CVD). The EC-EV ability to elicit either detrimental or restorative effects on target EC is thought to be, in part, due to horizontal transfer of their mitochondrial cargo. To understand the role of mitochondrial cargo in EC-EV paracrine effects, large EV were collected from media of cultured human EC, and the number of mitochondria-carrying EV (mitoEV), EV mitochondrial cargo mass, and mitoEV quality/polarization were quantified. EC activation with tumor necrosis factor (TNF)-α caused an increased release rate of EV (TNF-EV), including mitoEV that carried a larger and more depolarized mitochondrial cargo, compared to EV released from control EC (C-EV). EC co-treatment with TNF-α and the mitochondria-targeted antioxidant MitoTEMPO restored both the mitochondrial cargo quality and the number of mitoEV carrying polarized mitochondria to levels similar to C-EV. TNF-EV, but not C-EV, dose-dependently upregulated inflammatory gene expression in target naïve EC. Fluorescence microscopy showed the EV mitochondrial cargo to transfer and colocalize with the target EC mitochondrial network. Mitochondrial cargo depolarization of C-EV using carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone was sufficient for those EV to trigger inflammation in target naïve EC. In conclusion, the mitochondrial redox state of donor EC regulates mitoEV mitochondrial cargo quality that, at least in part, determines their capacity to cause target EC dysfunction and promote CVD. The mitochondrial membrane potential (ΔΨm) in EC-mitoEV may be a new biomarker and therapeutic target in vascular biology and medicine.

Keywords:  Extracellular vesicles; Inflammation; Mitochondria; Mitochondrial membrane potential; Mitochondrial transfer; Vascular endothelial cell

DOI:  https://doi.org/10.1016/j.biopha.2025.118751
Cell Commun Signal. 2025 Nov 13. 23(1): 495

Hypoxia-preconditioning human bone marrow-derived mesenchymal stem cells induce high-quality mitochondrial transfer through gap junctions to alleviate ischemia-reperfusion injury in liver graft.

Xinling Luo, Weiqi Zeng, Erfeng Xiong, Ziming Wang, Jingsheng Huang, Meiqi Luo, Zhongxian He, Jinyu Liu, Dongdong Yuan.

   BACKGROUND: Amid the widespread scarcity of donor livers, mitigating ischemia-reperfusion injury (IRI) of liver grafts is vital for ensuring early recovery of post-transplant liver function. Human bone marrow-derived mesenchymal stem cells (hBMSCs) have shown potential in alleviating IRI damage by regulating mitochondrial function. Hypoxia-preconditioning hBMSCs (hypo-hBMSCs) have shown considerable promise in enhancing therapeutic efficacy, yet the underlying mechanism remain to be elucidated. Therefore, this study aims to explore the role of hypo-hBMSCs in alleviating hepatic IRI and uncover their potential mechanisms, with the goal of offering new strategies for the application of hBMSCs in liver protection after transplantation.
METHODS: Initially, we investigated the impact of hypoxia preconditioning on the quality of hBMSCs mitochondria and whether hypo-hBMSCs can alleviate IRI damage in liver grafts by transferring mitochondria. Subsequently, by employing the enhancer RA and the inhibitor Gap26 to modulate the function of gap junctions (GJs) in vivo and in vitro, we confirmed their crucial role in the process of hypo-hBMSCs transferring mitochondria to hepatocytes. Ultimately, through bioinformatics analysis, Co-IP, siRNA and overexpression, we demonstrate that the up-regulated Cx43 and Cx32 in hypo-hBMSCs can form homotypic Cx43-GJs and Cx32-GJs with hepatocytes, thereby enhancing the transfer of mitochondria.
RESULTS: The results indicate that hypoxia preconditioning diminishes superoxides accumulation and elevates the mitochondrial membrane potential by inducing mitophagy in hBMSCs, consequently improving mitochondrial quality. Upon administration via portal vein injection, hypo-hBMSCs significantly mitigate hepatic IRI. Compared with hBMSCs, hypo-hBMSCs are capable of transferring more mitochondria to hepatocytes through GJs. When the function of GJs is modulated by the enhancer RA or the inhibitor Gap26, the efficiency of mitochondrial transfer correspondingly shifts. Further investigation uncovers that hypo-hBMSCs prompts an upsurge in the expression of Cx43 and Cx32 (not Cx26). Nevertheless, these proteins are unable to form heterotypic GJs (Cx43-Cx32-GJs) with hepatocytes; instead, they form homotypic Cx43-GJs and Cx32-GJs, which facilitate the transfer of mitochondria between hypo-hBMSCs and hepatocytes.
CONCLUSION: Hypo-hBMSCs can enhance mitochondrial quality by inducing mitophagy. Meanwhile, they can up-regulate Cx43 and Cx32 to form homotypic Cx43-GJs and Cx32-GJs with hepatocytes, thereby transferring more high-quality mitochondria to hepatocytes to exert a protective effect.

Keywords:  Gap junctions; HBMSCs; Hepatic ischemia-reperfusion injury; Hypoxia preconditioning; Mitochondrial transfer

DOI:  https://doi.org/10.1186/s12964-025-02497-1
Stem Cells Transl Med. 2025 Nov 14. pii: szaf059. [Epub ahead of print]14(11):

Platelets facilitate fat grafting by mitochondrial transfer and reducing oxidative stress in adipose-derived stem cells.

Chen Ke, Kaibo Liu, Wanying Chen, Zhongming Cai, Fangfang Yang, Qing Wei, Yucang He, Jingping Wang, Liqun Li, Binting Ni.

  Autologous fat grafting (AFG), characterized by a broad tissue source and absence of immune rejection, is extensively utilized in plastic surgery. Despite its advantages, AFG is frequently challenged by a high rate of fat resorption and limited volume retention. Recent studies have increasingly focused on integrating platelet-related preparations with adipose tissue to enhance graft survival rates. These investigations have consistently demonstrated the beneficial effects of platelets and their derivatives on adipose-derived stem cells (ADSCs), facilitating improved outcomes in fat transplantation. Nevertheless, the precise mechanisms governing the interaction between platelets and ADSCs remain insufficiently understood. We investigate the potential of platelets to augment the antioxidant stress capacity of ADSCs through mitochondrial transfer, thereby contributing to enhanced fat graft viability. Experimental results revealed that platelets significantly promoted ADSC proliferation, migration, metabolic activity, and mitochondrial function. Co-culture of oxidative stress-induced ADSCs with platelets resulted in improved cell viability and a marked reduction in reactive oxygen species (ROS) levels. The mitochondrial transfer from platelets to ADSCs, confirmed via fluorescent labeling, played a pivotal role in restoring mitochondrial function and decreasing glucose consumption under stress conditions. Furthermore, in a murine subcutaneous fat graft model, platelets exhibited a protective effect during the early oxidative stress phase, as evidenced by reduced ROS and malondialdehyde levels, increased glutathione expression, attenuated fibrosis, enhanced graft vascularization, and improved long-term survival. These findings suggest that platelet-mediated mechanisms, including mitochondrial transfer, may contribute to protecting ADSCs and improving fat graft outcomes.

Keywords:  adipose-derived stem cells; fat transplantation; plastic surgery; platelets

DOI:  https://doi.org/10.1093/stcltm/szaf059