bims-mitrat 2026-08-23 papers

Clin Exp Metastasis. 2026 Aug 19. pii: 43. [Epub ahead of print]43(5):

Platelet-derived mitochondrial transfer in cancer metastasis: mechanisms, functional consequences, and translational opportunities.

Farshad Heydari, Soheila Fahmi, Sameer Alqassimi, Nasrin Mansuri, Rithab Ibrahim Al-Samawi, Fatemeh Mozaffari, Michael R Hamblin, Jalal Naghinezhad.

Cancer metastasis is a multistep and highly inefficient process that depends on reciprocal interactions between tumor cells and the host microenvironment. Among the most important host contributors, platelets have emerged as active facilitators of metastatic dissemination, supporting the survival of circulating tumor cells, immune evasion, endothelial arrest, extravasation, and early colonization. More recently, platelet-derived mitochondrial transfer has been recognized as a novel mechanism by which platelets may enhance tumor aggressiveness through metabolic reprogramming. This review critically synthesizes the current literature on platelet-mediated mitochondrial transfer in cancer, with emphasis on its biological mechanisms, functional consequences, and translational implications. Emerging evidence in selected osteosarcoma and triple-negative breast cancer models indicates that activated platelets can donate functional mitochondria to cancer cells through direct contact and microparticle-mediated pathways, potentially increasing oxidative phosphorylation, ATP production, redox adaptability, proliferative capacity, and migratory behavior. Mechanistically, platelet mitochondrial transfer may involve pathways linked to mitochondrial quality control and trafficking, including PINK1/Parkin-MFN2 signaling, while also intersecting with broader platelet-tumor crosstalk that promotes epithelial-mesenchymal transition, anoikis resistance, and immune escape. In parallel, platelet-derived mitochondrial cargo and related extracellular vesicle signatures may offer new opportunities for liquid biopsy-based biomarker development. However, major challenges remain, including the need for rigorous in vivo validation, discrimination of intact mitochondria from fragmented mitochondrial material, and clarification of context-dependent effects across tumor types. Collectively, platelet-derived mitochondrial transfer represents an emerging layer of intercellular communication that may link thrombosis, metabolism, and metastasis, and it offers promising avenues for both biomarker discovery and therapeutic intervention.

Keywords: Cancer metastasis; Extracellular vesicles; Immune evasion; Liquid biopsy; Metabolic reprogramming; Mitochondrial transfer; Platelet-derived mitochondria; Platelet–tumor interaction

DOI: https://doi.org/10.1007/s10585-026-10424-y

J Dent Res. 2026 Aug 21. 220345261473588

Dental Pulp Stem Cells Transfer Mitochondria via Tunneling Nanotubes to Drive Hypoxic Angiogenesis.

S Yang, J Liu, D S Thalakiriyawa, J Liu, X Yang, C K Y Yiu, W L Dissanayaka.

The dental pulp resides within a rigid dentin chamber with a limited blood supply, creating a hypoxic environment that impedes tissue regeneration. While growth factor signaling in pulpal revascularization is well documented, the direct cellular mechanisms that protect endothelial cells (ECs) from hypoxia-induced apoptosis remain unclear. This study identifies intercellular mitochondrial transfer (MT) from dental pulp stem cells (DPSCs) to ECs as a critical survival and angiogenic mechanism under hypoxic stress. Using MitoTracker labeling and flow cytometry, we demonstrated that mitochondria are preferentially transferred from DPSCs to ECs, a process significantly upregulated by hypoxia. We found that contact-dependent mechanisms involving tunneling nanotube-like structures contribute to MT, as cytochalasin B treatment or Miro1 knockdown in DPSCs significantly reduced MT and impaired EC function. To assess the impact of this organelle exchange, we isolated mitochondria-recipient (Mito+) and nonrecipient (Mito-) ECs for analysis. Mito+ ECs exhibited enhanced mitochondrial membrane potential, improved energy metabolism, and yielded superior tube-forming capacity as compared with Mito- ECs. Furthermore, MT significantly reduced EC apoptosis under cobalt chloride-induced hypoxic stress. The in vivo Matrigel plug assay showed that inhibiting MT from DPSCs, genetically or by inhibiting mitochondrial respiration, markedly suppressed DPSC-supported angiogenesis and increased EC apoptosis. Mechanistically, RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that MT revives the EC transcriptome and activates the PI3K-AKT signaling pathway. Immunofluorescence confirmed upregulation of AKT signaling in recipient ECs and colocalization of P-AKT with transferred mitochondria. Furthermore, inhibition of AKT signaling with MK-2206 abolished the proangiogenic and prosurvival role associated with MT, suggesting a direct regulatory role. Collectively, these findings establish MT as a vital metabolic lifeline that prevents EC collapse and drives DPSC-supported angiogenesis in the hypoxic pulp during the vulnerable window of pulpal restoration, thereby emphasizing MT as a transformative regenerative endodontic target.

Keywords: apoptosis; cell communication; cell hypoxia; cell survival; energy metabolism; mesenchymal stem cells

DOI: https://doi.org/10.1177/00220345261473588

Research (Wash D C). 2026 ;9 1410

In Situ Biomineralization Enhances Mitochondrial Transplantation to Differentiating Osteoclast Precursors for Suppressing Cancer-Induced Osteolysis.

Yu Zhang, Changpeng Liu, Pengzhen Zhuang, Chengcheng Li, Huan Zhang, Yuanyuan Liu, Yu Chen, Wu Yang, Longxi Wu, Yawei Du, Wenguo Cui, Hongbo Zhang.

Cancer-induced bone osteolysis is a common complication of multiple malignancies and may actively contribute to bone metastasis. Its core pathology is closely associated with mitochondrial metabolic dysfunction during osteoclast differentiation. In this study, a mitochondrial transplantation strategy based on in situ biomineralization (Mito@ZIF@RGD) was developed to overcome multiple delivery barriers in differentiating osteoclast precursor cells. A zeolitic imidazolate framework-8 (ZIF-8) shell was formed via the in situ self-assembly of Zn2+ and 2-methylimidazole on the mitochondrial membrane, thereby enhancing mitochondrial stability. Meanwhile, cyclic RGD (arginine-glycine-aspartic acid) peptides were coordinated with exposed Zn2+ sites on the outer shell to promote αvβ3-mediated uptake during osteoclast differentiation. Furthermore, the sustained Zn2+ release from the ZIF-8 biomineralization reshaped intracellular ionic homeostasis, thereby improving the durability of therapeutic efficacy following mitochondrial transplantation. In vitro experiments demonstrated that ZIF-8 encapsulation stabilized mitochondria and enabled sustained adenosine triphosphate production for more than 48 h. RGD modification improved cellular uptake efficiency by approximately 55% in differentiating osteoclast precursors, while the mildly acidic microenvironment triggered the coordinated release of mitochondria and Zn2+, effectively reducing intracellular reactive oxygen species levels and osteoclast formation. In vivo, Mito@ZIF@RGD treatment promoted the recovery of bone mineral density, suppressed osteoclast surface area formation by approximately 30%, and preserved bone microstructural integrity. Therefore, as a stable, specific, and durable mitochondrial transplantation platform modulating cellular metabolism during osteoclast differentiation, Mito@ZIF@RGD represents a stable and promising platform for the treatment of cancer-induced osteolysis and other metabolic imbalance-associated bone diseases.

DOI: https://doi.org/10.34133/research.1410

Adv Healthc Mater. 2026 Aug 16. e71510

Stem Cell-Derived Mitochondria-Enriched Preservation Solutions as Organelle-Based Therapeutic Strategy for Cold Storage of Liver and Kidney.

Fang Lin, Jianxin Jiang, Jing Liu, Yue Ding, Kexin Ma, Jiyuan Wang, Xueyang Zheng, Yu Chen, Shu Han, Xiaoting Liang.

Organ preservation remains a critical challenge in transplantation, primarily due to hypothermia-induced oxidative stress and metabolic dysfunction. Here, we report a mitochondria-enriched, cell-free preservation strategy by supplementing standard preservation solutions with freshly isolated mitochondria derived from human induced pluripotent stem cell-mesenchymal stem cells (MSC-mt). MSC-mt retained intact ultrastructure and functional biophysical properties. In vitro, MSC-mt were internalized by hepatocyte- and kidney-derived cells, reduced oxidative stress, preserved ATP levels, and attenuated apoptosis under cold stress. Ex vivo, MSC-mt improved liver preservation in University of Wisconsin (UW) solution, reducing sinusoidal edema, apoptosis, ALT/AST release, MDA accumulation, and oxidative DNA damage while enhancing SOD activity and preserving mitochondrial content. Human-specific mitochondrial signals remained detectable within preserved hepatic tissue. In a warm reoxygenation model, MSC-mt enhanced ATP recovery and reduced tissue injury and oxidative damage following cold storage. In kidneys, MSC-mt provided stronger protection than fibroblast- or adipose-derived mitochondria across both HC-A and UW solutions. Mechanistically, MSC-mt showed higher total and phosphorylated PINK1 levels and greater Parkin co-localization than fibroblast-derived mitochondria, while mitophagy inhibition partially reversed their antioxidant effects. These findings establish MSC-mt as a cell-free mitochondrial strategy for improving hypothermic organ preservation.

Keywords: liver preservation; mesenchymal stem cell‐derived mitochondria; organ preservation; renal preservation

DOI: https://doi.org/10.1002/adhm.71510

Extracell Vesicle. 2026 Jun;pii: 100100. [Epub ahead of print]7

Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.

Paromita Paul Pinky, Zhong-Min Wang, Purva Khare, Jhanvi R Jhaveri, Abigail Sullivan, Vivek Basudkar, Krithika S Rao, Audrey Lawrence, Adithri Pingali, Kandarp M Dave, Donna B Stolz, Ming Sun, Si-Yang Zheng, Sruti S Shiva, Carol Milligan, Osvaldo Delbono, Devika S Manickam.

Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1G93A transgenic mouse model of ALS.

Keywords: ALS; EVs; extracellular vesicles; large EVs; mitochondria; motor neurons; small EVs; spinal cord

DOI: https://doi.org/10.1016/j.vesic.2025.100100