bims-mitrat 2026-01-25 papers

Transl Stroke Res. 2026 Jan 21. 17(1): 17

Recent Advances in Mitochondrial Transplantation for Ischemic Stroke: A Review of in Vitro and in Vivo Studies.

Zixian Mei, Weijie Zhong, Tanjun Deng, Xuchen Meng, Xin Lv, Jiexi Xiao, Yi Li.

Ischemic stroke is a common and devastating disease that imposes a huge burden on global health and the economy. Mitochondrial dysfunction is a key feature of cerebral ischemia-reperfusion injury (CIRI). Mitochondrial transplantation, an emerging neuroprotective strategy that introduces exogenous mitochondria into a living organism, has shown great potential in various neurological diseases. However, significant challenges persist, including the lack of standardized dosing regimens and unclear mechanisms regarding long-term mitochondrial engraftment. While initial clinical trials have demonstrated the safety of this approach, the field is currently at a pivotal juncture requiring rigorous translation from preclinical success to proven clinical efficacy. This review summarizes the in vitro and in vivo research findings on mitochondrial transplantation in stroke models, with the aim of providing a basis for the clinical translation of this technology.

Keywords: Cerebral ischemia-reperfusion injury; Ischemic stroke; Mitochondrial transfer; Mitochondrial transplantation

DOI: https://doi.org/10.1007/s12975-025-01401-w

Adv Sci (Weinh). 2026 Jan 22. e23368

Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.

Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.

Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.

Keywords: chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics

DOI: https://doi.org/10.1002/advs.202523368

J Transl Med. 2026 Jan 19.

Astrocytic mitochondrial transfer: a new horizon for metabolic rescue and precision therapy in ischemic stroke.

Xin Lan, Chuxin Zhang, Zilin Ren, Jialin Cheng, Congai Chen, Yuxiao Zheng, Jinhua Han, Yang Zhao, Jiaming Li, Fafeng Cheng, Xueqian Wang, Qingguo Wang, Changxiang Li.

Ischemic stroke (IS) remains a leading cause of global mortality and neurological disability, with neuronal mitochondrial dysfunction as a central pathological mechanism. Astrocytes, the metabolic custodians of the central nervous system, exert neuroprotection by transferring functional mitochondria to compromised neurons via tunneling nanotubes (TNTs), extracellular vesicles (EVs), connexin 43 (Cx43) mediated gap junctions, and membrane fusion. These transfers replenish neuronal energy reserves, mitigate oxidative stress, and enhance synaptic plasticity. This review systematically delineates the molecular mechanisms of astrocyte-mediated mitochondrial transfer, its regulatory roles in oxidative stress, calcium dyshomeostasis, and ferroptosis, and its therapeutic potential in IS. Experimental models demonstrate that pharmacological enhancement of mitochondrial transfer or exogenous transplantation significantly reduces infarct volume and improves neuronal survival. However, clinical translation faces challenges including low mitochondrial viability, immune rejection, and inefficient delivery. Future research should integrate gene-editing tools, nanocarrier systems, and organoid models to optimize mitochondrial dynamics and develop precision therapies. By bridging mechanistic insights with translational innovations, astrocytic mitochondrial transfer emerges as a groundbreaking strategy for ischemic stroke treatment.

Keywords: Astrocyte; Ischemic stroke; Mitochondrial transfer; Neuron; Neuroprotection

DOI: https://doi.org/10.1186/s12967-025-07290-9

Front Pharmacol. 2025 ;16 1725973

Bone-targeted mitochondrial delivery via magnetic-temperature responsive artificial cells for repairing age-related fractures.

Shihao Nie, Yue Yu, Rong Yan, Taoran Liu, Yue Du, Zhuojing Luo, Shengyou Li, Jinghui Huang.

Background: Age-related bone diseases, such as osteoporosis and degenerative joint disorders, pose a significant global health challenge, leading to over 9 million fractures annually, which not only diminishes quality of life but also imposes a substantial socioeconomic burden on healthcare systems. A major clinical obstacle in the aging population is the significantly reduced regenerative capacity of bone, often resulting in delayed fracture healing or nonunion fractures. Mitochondria, as the central regulators of cellular energy metabolism, are essential for determining cell fate and supporting tissue regeneration. However, age-associated mitochondrial dysfunction critically impairs these processes. While transplanting healthy mitochondria is a promising therapeutic strategy, its efficacy is severely limited by poor targeting efficiency and inherent fragility of mitochondria in circulation. Developing an efficient mitochondrial transplantation for elderly fractures is of great importance.
Methods: We constructed artificial cell microspheres (Fmito@ACs) containing mitochondria of fetal mouse mesenchymal stem cells and conducted systematic characterization of them. In vitro experiments evaluated the effects of Fmito@ACs on the functions of primary osteoblasts, and its role in delaying cellular senescence was analyzed through β-galactosidase staining and immunofluorescence analysis of senescence markers (P21 and γH2A.X). Its ability to restore mitochondrial function was assessed by measuring ROS, morphology, and energy metabolism. In animal experiments, labeled Fmito@ACs were tracked using IVIS Spectrum system, and their targeted accumulation at fracture sites guided by an external magnetic field was verified. The biosafety of the system was evaluated via H&E staining and hepatic/renal function parameters. Bone healing was monitored via micro-CT, X-ray, and histology on days 7, 14, and 21, while related gene expression and molecular mechanisms were analyzed by qPCR and transcriptome sequencing.
Results: Fmito@ACs were successfully constructed and characterized, indicating a protective effect on mitochondria. The system ameliorated senescence in aged BMSCs, promoting osteogenesis by enhancing mitochondrial fusion and aerobic glycolysis. In an aged fracture model, Fmito@ACs showed targeted accumulation and biosafety, significantly improving healing.
Conclusion: As an efficient mitochondrial-targeted delivery system, Fmito@ACs fully exploits the anti-aging effects of young mitochondria, providing a new strategy and theoretical basis for the treatment of age-related fractures.

Keywords: age-related fractures; anti-aging; artificial cells; magnetic-temperature responsive; mitochondria

DOI: https://doi.org/10.3389/fphar.2025.1725973

MedComm (2020). 2026 Feb;7(2): e70590

Mitochondrial Intercellular Transfer via Platelets After Physical Training Exerts Neuro-Glial Protection Against Cerebral Ischemia.

Toshiki Inaba, Nobukazu Miyamoto, Kenichiro Hira, Chikage Kijima, Yoshifumi Miyauchi, Hai-Bin Xu, Kazo Kanazawa, Yuji Ueno, Nobutaka Hattori.

While thrombolytic therapy can be effective for stroke, many patients are unable to benefit due to time restrictions. In an aging society, sarcopenia, a condition marked by reduced muscle volume, often worsens recovery after stroke. Our study explored how mitochondria, which are abundant in muscle, could aid in stroke recovery through exercise-induced migration. Using mouse models of chronic hypoperfusion and ischemia, alongside in vitro studies with rat primary cells under oxygen-glucose deprivation and CoCl2 exposure, we found that treadmill exercise protected against white matter injury, myelin loss, astroglial formation, and memory deficits observed 28 days post-hypoperfusion. In acute ischemia models, training reduced glial activation and post-stroke complications. Exercise increased mitochondrial levels in muscle and blood, facilitating their migration between tissues via platelets. In vitro, the addition of muscle-derived mitochondria enhanced the survival of neurons, astrocytes, and oligodendrocytes. Notably, platelets carrying mitochondria from treadmill-trained mice significantly improved ischemic white matter injury and mitigated post-stroke complications. This study highlights mitochondria as a critical part of the secretome, suggesting that muscle-derived mitochondria might play a role in the protective effects of remote ischemic preconditioning. Cell-cell mitochondrial migration, therefore, could offer a promising new approach to reducing post-stroke complications and vascular dementia.

Keywords: cerebral infarction; mitochondrial migration; platelet therapy; prolonged cerebral hypoperfusion; white matter injury

DOI: https://doi.org/10.1002/mco2.70590

Cardiovasc Res. 2026 Jan 20. pii: cvag014. [Epub ahead of print]

Cardiomyocyte derived extracellular mitochondria in activation of macrophages during oxidative stress.

Lenee Shrestha, Haiwei Gu, Taylor Satterlee, Suizi He, Qin M Chen.

AIMS: Mitochondria serve as central hubs for aerobic metabolism and regulators of cell fate. Damage to mitochondria induced by oxidative stress contributes to cardiac injury. We investigate whether oxidative stress causes the release of mitochondrial into the extracellular space and whether these extracellular mitochondria (EM) mediate the detrimental effect of oxidative stress.
METHODS AND RESULTS: AC16 cardiomyocytes were exposed to sublethal doses of H2O2 to collect mitochondria released into the conditioned culture medium. These EM were compared with intracellular mitochondria (IM) for morphology, size, membrane potential, and metabolic profile using LC-MS/MS based metabolomics. Cellular ceramide content was measured by lipidomics to determine the role of ceremide synthesis in mitochondrial release. EM were tested for the ability to activate THP-1 macrophages.Oxidants caused an increase of EM. While EM from stressed cells did not show significant difference from those of non-stressed cells in overall morphology, size or surface charge, EM exhibited disrupted cristae structure, smaller size, reduced membrane potential, and decreased levels of NAD, ATP, ADP and AMP compared to IM. H2O2 treatment upregulated several ceramide species in AC16 cells and inhibition of ceramide synthesis markedly reduced EM released under oxidative stress. Functionally, EM activated M1 and M2 like macrophages, as indicated by increased expression of the cytokine markers TNFα and CD163.
CONCLUSIONS: Oxidative stress enhanced the release of mitochondria from cardiomyocytes into the extracellular space. These EM differ from IM in their smaller sizes, reduced membrane potential, and depressed metabolic state. At high abundance, EM act as mediators that promote macrophage activation.

Keywords: ceramide; macrophages; metabolomics; mitochondrial quality control

DOI: https://doi.org/10.1093/cvr/cvag014