bims-mitrat 2025-10-05 papers

Research (Wash D C). 2025 ;8 0927

Intercellular Nanotube Mitochondrial Transplantation Strategy Mediating T Cell "Supercharging".

The functional exhaustion of T cells in the tumor immune microenvironment is closely related to mitochondrial dysfunction. Current mitochondrial-targeted strategies have failed to restore the mitochondrial impaired function effectively. Mitochondrial transplantation technology has brought a revolution to the treatment of organelle-related diseases. Here, we first summarize the therapeutic potential and available platforms for mitochondrial transplantation, and focus on a type of mitochondrial transplantation technology mediated by tunneling nanotubes. This technology transfers functional mitochondria from bone marrow mesenchymal stem cells to CD8+ T cells, obtaining "supercharged T cells", which markedly enhance the metabolic adaptability and antitumor efficacy of T cells. It provides new ideas and technical platforms for the application of organelle medicine in tumor immunotherapy.

DOI: https://doi.org/10.34133/research.0927

Front Immunol. 2025 ;16 1668281

Mitochondrial transfer/transplantation in lung injury: mechanism, therapeutic potential, and clinical application.

Ling-Jie Wang, Peng-Fei Guo, SongOu Zhang, Sai Wang, Yi-Zhao Chen, Hong-Wang Yan, Xue-Lin Zhang.

Lung injury has become a critical clinical problem that urgently requires resolution due to its high morbidity, high mortality, and the limitations of existing treatment methods. Mitochondrial dysfunction, as the core mechanism of lung injury, promotes disease progression through energy metabolism imbalances, oxidative stress, and exacerbated inflammatory responses. Recent studies have found that intercellular mitochondrial transfer, acting as a "transcellular rescue" mechanism, can deliver functional mitochondria through pathways such as tunneling nanotubes, exosome. This process provides a novel approach to replenish energy for damaged cells, regulate inflammation, and repair tissues. In various lung injury models, mitochondrial transfer/transplantation has been shown to improve alveolar-capillary barrier function, reduce collagen deposition, inhibit the release of inflammatory factors, and restore mitochondrial membrane potential. This is particularly evident in conditions such as acute lung injury, pulmonary fibrosis, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, where it shows significant therapeutic potential. The combination of diverse delivery methods and multi-source mitochondria provide a flexible strategy for clinical application. In summary, mitochondrial transfer, as an emerging intercellular communication and rescue mechanism, provides a promising new direction for the precision treatment of lung injury.

Keywords: ALI; ARDS; COPD; lung injury; mitochondrial transfer

DOI: https://doi.org/10.3389/fimmu.2025.1668281

Bioeng Transl Med. 2025 Sep;10(5): e70027

Mitochondrial and photosynthetic therapy: A crucial strategy for remodeling cellular metabolic function.

Muhammad Samee Mubarik, Zizhen Zhao, Mehdi Khoshnamvand, De-Sheng Pei, Ailing Fu.

Extranuclear organelle transplantation, an emerging field in cell biology and bioengineering, presents innovative therapeutic possibilities by transferring organelles such as mitochondria between cells or across species. In living organisms, mitochondria and chloroplasts are closely related to converting substances and energy within cells. Transplantation therapy of mitochondria seeks to rebuild cell metabolic function in diseased or damaged cells and has broad application potential in treating metabolic diseases. The therapies provide a distinctive technology for cellular restoration by targeting energy generation at the organelle level, which will offer new energy resources for animal cells. At present, mitochondrial transplantation therapy has been applied as a novel approach to rescue patients in clinical settings, and chloroplast-based transplantation endows animal cells to utilize light energy (photosynthetic animal cells). In this review, we discuss the exciting development and application prospects of mitochondrial and photosynthetic therapy in biomedicine. The technology of extranuclear transplantation would exert innovative and profound impacts on biological therapy.

Keywords: cellular new energy resources; chloroplasts; clinical applications; mitochondria

DOI: https://doi.org/10.1002/btm2.70027

Bioeng Transl Med. 2025 Sep;10(5): e70040

Enhancement of spinal cord injury repair in rats using photo-crosslinked GelMA hydrogel combined with mitochondrial transplantation.

Wenyong Gao, Can Tang, Diancheng Hang, Hao Chen, Dongsheng Li, Youjie Yan, Wuchang Wang, Hao Peng, Xianmin Wang, Enpeng Zhang, Min Wei, Hengzhu Zhang, Xiaodong Wang.

Acute spinal cord injury (SCI) induces mitochondrial oxidative stress, cellular bioenergetic crises, impaired protein degradation, and subsequent degeneration, resulting in increased neuronal vulnerability. Transplantation of exogenous mitochondria to the injury site mitigates cellular energy crises and counteracts neurodegeneration; however, the limited efficacy of mitochondrial transplantation alone constrains its therapeutic potential. In this study, we established a right-sided spinal cord hemisection model at the T10 thoracic segment in rats and transplanted a methacrylate-based gelatin (GelMA) hydrogel containing active mitochondria at the injury site to assess its therapeutic effects and underlying mechanisms. Our findings indicate that GelMA hydrogel combined with mitochondrial transplantation provides superior therapeutic benefits for SCI compared to mitochondrial transplantation alone. GelMA hydrogel enables sustained mitochondrial release at the injury site, supplying energy, upregulating NF200 expression, and promoting axonal regeneration. Additionally, it enhances M2 macrophage accumulation and improves the local inflammatory microenvironment. The structural framework of GelMA hydrogel further supports axonal regeneration. Footprint gait analysis and Basso, Beattie, and Bresnahan (BBB) motor scoring demonstrated that GelMA hydrogel combined with mitochondrial transplantation significantly improves motor function in the right hind limb of rats with SCI. Consequently, GelMA hydrogel combined with mitochondrial transplantation offers a viable and promising approach for treating spinal cord injury.

Keywords: GelMA hydrogel; mitochondrial transplantation; spinal cord injury

DOI: https://doi.org/10.1002/btm2.70040

Neurochem Res. 2025 Oct 04. 50(5): 317

The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.

Vaishali Walecha, Pratibha M Luthra.

The medical field has spent many years investigating Parkinson's disease (PD), primarily focusing on its main pathogenic feature, dopaminergic neuronal degeneration. Recent studies indicate that PD develops through a complex pathogenic model that links mitochondria to astrocytes and neurons, creating a destructive metabolic loop, a protein aggregation cycle, and oxidative stress. This review examines how mitochondria integrate with astrocytes and neurons in the "triad hypothesis," offering a multifaceted perspective on PD progression. Despite being previously overlooked, we have observed that astrocytic mitochondria play a central role in maintaining neuroprotection and homeostasis. Given that, dysfunctional mitochondria in astrocytes and neurons lead to metabolic failure, compromised glutamate regulation, while also enhancing α-synuclein aggregation, amplifying neuroinflammation, ferroptotic vulnerability and oxidative stress. Henceforth, this report discusses current insights into astrocyte-neuron metabolic coupling, mitochondrial quality control, and lipid redox imbalance, highlighting the role of astrocytic mitochondria as a strong therapeutic strategy. We discuss experimental and translational approaches that aim to restore triad integrity, including mitophagy enhancement, metabolic reprogramming, mitochondrial transfer, and astrocyte-to-neuron reprogramming. By positioning astrocytic mitochondria at the core of PD pathogenesis, this review advocates novel interventions focused on glial metabolic resilience. This integrated approach addresses three major pathogenic axes. It offers promising potential for disease modification and developing effective therapeutics beyond symptomatic dopamine replacement to correct neurodegenerative conditions.

Keywords: Astrocytic mitochondria; Calcium signalling; Ferroptosis; Mitochondrial dysfunction; Mitochondrial transfer; Neurodegeneration; Neuroinflammation; Neuron-astrocyte interaction; Oxidative stress; Parkinson’s disease (PD); α-Synuclein aggregation

DOI: https://doi.org/10.1007/s11064-025-04559-9

JHEP Rep. 2025 Oct;7(10): 101484

Stiffness-activated hepatic stellate cells boost HCC migration via TGM2/ITGB1-mediated matrix remodeling and mitochondrial transfer.

Man Wang, Yannan Xu, Yongbin Meng, Wei Xie, Jun Chen, Juan Du.

Background & Aims: High liver stiffness correlates with poor outcomes in hepatocellular carcinoma (HCC). Prior studies focused on neoplastic cells rather than the tumor microenvironment. This study investigated how the tumor microenvironment, particularly mechanosignaling in hepatic stellate cells (HSCs), drives HCC progression.
Methods: The study examined the roles of transglutaminase 2 (TGM2) and integrin β1 (ITGB1) in HSCs under mechanical stress through proteomics, cell contraction assays, and protein interactions. It also analyzed gene expression data from 178 patients with HCC and cirrhosis to assess the impact of TGM2 and ITGB1 on overall survival (OS). Mitochondrial transfer and cell migration were observed using confocal microscopy, and the effect of TGM2/ITGB1 on extracellular matrix (ECM) remodeling and HCC recurrence was studied in a rat liver cancer model.
Results: We showed that HSC activation under matrix stiffness relied on ITGB1 mechanosignaling, with high cell-surface TGM2 expression required for ITGB1 activation. This process activated downstream CAV1, which in turn stabilized ITGB1 expression. Moreover, high co-expression of TGM2/ITGB1 (R = 0.77, p <2.2 × 10-16) was negatively correlated with OS. Interestingly, we found massive mitochondrial transfer in hybrid co-cultures between cancer-associated fibroblasts (CAFs) and Huh7 cells by tunneling nanotubes under high stiffness (p = 0.0095), which appeared to be associated with TGM2/ITGB1. Huh7 cells with CAF-derived mitochondria exhibited enhanced migration under increased substrate stiffness (p <0.0001). Accordingly, high liver stiffness activated CAFs, leading to ECM remodeling and postoperative recurrence of HCC. TGM2/ITGB1 was essential for matrix stiffness-driven HCC recurrence following surgery.
Conclusions: This study revealed a novel mechanism by which HSCs facilitate HCC progression under matrix stiffness, which may aid in the design of therapies for the clinical treatment of HCC.
Impact and Implications: Hepatic stellate cells (HSCs) undergo differentiation into cancer-associated fibroblasts (CAFs), which constitute the primary stromal cell population within the liver tumor microenvironment and are associated with poor prognosis in patients with hepatocellular cancer (HCC). The precise mechanisms through which CAFs facilitate HCC progression remain incompletely elucidated. In this study, we emphasize the role of transglutaminase 2-medated integrin β1 in the activation of HSCs induced by increased matrix stiffness. Furthermore, we explore how enhanced matrix stiffness promotes mitochondrial transfer, thereby facilitating the migration of HCC cells. These insights may inform the development of targeted therapeutic strategies for the clinical management of HCC.

Keywords: HCC; Hepatic stellate cells; Matrix stiffness; Mitochondrial transfer; Postoperative recurrence; TGM2/ITGB1

DOI: https://doi.org/10.1016/j.jhepr.2025.101484