bims-mitrat 2025-08-03 papers

Life (Basel). 2025 Jun 23. pii: 998. [Epub ahead of print]15(7):

Feasibility of Xenogeneic Mitochondrial Transplantation in Neuronal Systems: An Exploratory Study.

Eriko Nakamura, Tomoaki Aoki, Cyrus E Kuschner, Yusuke Endo, Jacob S Kazmi, Tai Yin, Ryosuke Takegawa, Lance B Becker, Kei Hayashida.

Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the dose-dependent uptake and molecular effects of xenogeneic mitochondrial transplantation (xeno-MTx) using rat-derived mitochondria in mouse neuronal systems. HT-22 hippocampal neuronal cells and a murine model of cardiac arrest-induced global cerebral ischemia were used to assess mitochondrial uptake, gene expression, and mitochondrial DNA presence. Donor mitochondria were isolated from rat pectoralis muscle and labeled with MitoTracker dyes. Flow cytometry and confocal microscopy revealed a dose-dependent increase in donor mitochondrial uptake in vitro. Quantitative PCR demonstrated a corresponding increase in rat-specific mitochondrial DNA and upregulation of Mfn2 and Bak1, with no changes in other fusion, fission, or apoptotic genes. Inhibitor studies indicated that mitochondrial internalization may involve actin-dependent macropinocytosis and cholesterol-sensitive endocytic pathways. In vivo, rat mitochondrial DNA was detected in mouse brains post-xeno-MTx, confirming donor mitochondrial delivery to ischemic tissue. These findings support the feasibility of xeno-MTx and its dose-responsive biological effects in neuronal systems while underscoring the need for further research to determine long-term functional outcomes and clinical applicability.

Keywords: cardiac arrest; ischemia–reperfusion; mitochondria; mitochondrial transplantation; neuron

DOI: https://doi.org/10.3390/life15070998

JACC Basic Transl Sci. 2025 Jul 25. pii: S2452-302X(25)00283-9. [Epub ahead of print]10(8): 101331

Harnessing Mitochondrial Transplantation to Target Vascular Inflammation in Cardiovascular Health.

Natalia Matiuto, Brandon Applewhite, Nicola Habash, Ana Martins, Bowen Wang, Bin Jiang.

Mitochondrial dysfunction is a key contributor to vascular inflammation in many cardiovascular diseases. This review explores mitochondrial transplantation as a promising strategy for addressing mitochondrial dysfunction and vascular inflammation. We discuss mitochondrial dysfunction across different vascular cell types and current clinical management strategies, highlighting the need for novel approaches that directly target mitochondrial health. We also present recent progress in mitochondrial transplantation across cardiac, neurovascular, and peripheral vascular applications in preclinical settings, as well as ongoing clinical trials. Important technical considerations, such as mitochondria sourcing, delivery routes, and storage, are discussed to facilitate future translation. By reinstating mitochondrial health and hence mitigating vascular inflammation, mitochondrial transplantation holds the potential to provide novel, targeted therapies for cardiovascular diseases, ultimately improving patient outcomes, reducing disease progression, and addressing unmet medical needs in vascular health. The translation of this technology into clinical practice could offer significant advances in the treatment of a wide range of cardiovascular conditions.

Keywords: endothelial dysfunction; mitochondrial dysfunction; mitochondrial transfer; oxidative stress; vascular inflammation

DOI: https://doi.org/10.1016/j.jacbts.2025.101331

Iran J Pharm Res. 2025 Jan-Dec;24(1):24(1): e159628

The Protective Effects of Mitochondrial Therapy Against Vincristine- Induced Nephrotoxicity in the Rat's Renal Proximal Tubular Cells.

Armaghan Lohrasbi, Abdollah Arjmand, Farzaneh Kamranfar, Mehdi Aghsami, Jalal Pourahmad.

Background: The application of vincristine (VCR) in treating a range of cancers is well-documented, showcasing its considerable effectiveness. Nevertheless, its clinical application is constrained by its impact on healthy tissues and various organ systems. Specifically, it can compromise kidney function, resulting in toxicological concerns. Studies have demonstrated that vincristine contributes to nephrotoxicity via the induction of oxidative stress.
Objectives: The present research focused on assessing the influence of mitochondrial transplantation in mitigating the mitochondrial and cellular toxicity associated with VCR in renal proximal tubular cells (RPTCs).
Methods: This investigation evaluated specific toxicity metrics, including cell death, reactive oxygen species (ROS) generation, decreased mitochondrial membrane potential (MMP), glutathione (GSH) concentration, succinate dehydrogenase (SDH) activity, lipid peroxidation (LPO), and adenosine triphosphate (ATP) levels. Freshly prepared active mitochondria were obtained from the kidneys of Wistar rats.
Results: The data demonstrated the cytotoxic effects of VCR on RPTCs. It was further observed that vincristine triggered oxidative stress, characterized by heightened ROS levels, diminished GSH content, decreased SDH activity, and increased lipid peroxidation. Furthermore, VCR caused notable damage to both mitochondrial and lysosomal membranes, along with a significant decrease in ATP content. The innovative strategy of mitochondrial transplantation mitigated oxidative stress, alleviated mitochondrial membrane damage, and prevented ROS-mediated apoptosis signaling induced by vincristine in RPTCs. Our results also indicated an increase in ATP levels within these cells.
Conclusions: Our investigation suggests that the proposed treatment modality may prove beneficial in addressing drug-induced nephrotoxicity.

Keywords: Mitochondria Transplantation; Nephrotoxicity; Oxidative Stress; Renal Proximal Tubular Cells; Vincristine

DOI: https://doi.org/10.5812/ijpr-159628

Int J Mol Sci. 2025 Jul 11. pii: 6645. [Epub ahead of print]26(14):

Causes of and Solutions to Mitochondrial Disorders: A Literature Review.

Vera Belousova, Irina Ignatko, Irina Bogomazova, Elena Sosnova, Svetlana Pesegova, Anastasia Samusevich, Evdokiya Zarova, Madina Kardanova, Oxana Skorobogatova, Anna Maltseva.

Mitochondria are currently of great interest to scientists. The role of mitochondrial DNA (mtDNA) mutations has been proven in the genesis of more than 200 pathologies, which are called mitochondrial disorders. Therefore, the study of mitochondria and mitochondrial DNA is of great interest not only for understanding cell biology but also for the treatment and prevention of many mitochondria-related pathologies. There are two main trends of mitochondrial therapy: mitochondrial replacement therapy (MRT) and mitochondrial transplantation therapy (MTT). Also, there are two main categories of MRT based on the source of mitochondria. The heterologous approach includes the following methods: pronuclear transfer technique (PNT), maternal spindle transfer (MST), Polar body genome transfer (PBT) and germinal vesicle transfer (GVT). An alternative approach is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. Transmission of defective mtDNA to the next generation can also be prevented by using these approaches. The development of a healthy child, free from genetic disorders, and the prevention of the occurrence of lethal mitochondrial disorders are the main tasks of this method. However, a number of moral, social, and cultural objections have restricted its exploration, since humanity first encountered the appearance of a three-parent baby. Therefore, this review summarizes the causes of mitochondrial diseases, the various methods involved in MRT and the results of their application. In addition, a new technology, mitochondrial transplantation therapy (MTT), is currently being actively studied. MTT is an innovative approach that involves the introduction of healthy mitochondria into damaged tissues, leading to the replacement of defective mitochondria and the restoration of their function. This technology is being actively studied in animals, but there are also reports of its use in humans. A bibliographic review in PubMed and Web of Science databases and a search for relevant clinical trials and news articles were performed. A total of 81 publications were selected for analysis. Methods of MRT procedures were reviewed, their risks described, and the results of their use presented. Results of animal studies of the MTT procedure and attempts to apply this therapy in humans were reviewed. MRT is an effective way to minimize the risk of transmission of mtDNA-related diseases, but it does not eliminate it completely. There is a need for global legal regulation of MRT. MTT is a new and promising method of treating damaged tissues by injecting the body's own mitochondria. The considered methods are extremely good in theory, but their clinical application in humans and the success of such therapy remain a question for further study.

Keywords: mitochondrial DNA; mitochondrial disorders; mitochondrial replacement therapy; mitochondrial transplantation therapy; review; three-parent baby

DOI: https://doi.org/10.3390/ijms26146645

Blood. 2025 Aug 01. pii: blood.2024028079. [Epub ahead of print]

Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.

Abhishek K Singh, Angelo D'Alessandro, Ashley Wellendorf, Daniel Gonzalez-Nieto, Matthew Kofron, Monika Dzieciatkowska, Leo Mejia, Luis Barrio, Marie-Dominique Filippi, Jose A Cancelas.

Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSC and their isolated mitochondria, we identified that Cx43 is present on inner and outer mitochondrial membranes of HSC/MPP, where it primarily regulates mitochondrial metabolism and ATP synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK and 2-oxoglutarate dehydrogenase (OGDH)-a rate liming enzyme in TCA cycle and electron transfer chain. During replicative stress, Cx43 deficient HSC/MPP fail to adapt metabolically, accumulate mitochondrial Ca2+, increase mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyper mitochondrial fragmentation and mitophagy by Drp1 dominant negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevent the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure function mutants indicate that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.

DOI: https://doi.org/10.1182/blood.2024028079

J Neurochem. 2025 Aug;169(8): e70170

Neural Stem Cell-Derived Extracellular Vesicles for Advanced Neural Repair.

Eduardo H Moretti, Ally L Y Lin, Luca Peruzzotti-Jametti, Stefano Pluchino, Sabah Mozafari.

The limited regenerative capacity of the central nervous system (CNS) severely hinders treatment of neurodegenerative and neuroinflammatory diseases. These conditions, frequently exacerbated by aging, share common hallmarks such as neuroinflammation, demyelination, and neuronal loss. While neural stem cells (NSCs) hold great therapeutic promise due to their paracrine effects, including extracellular vesicle (EV) release, direct transplantation presents significant challenges. This review focuses on NSC-derived EVs as a novel therapeutic strategy, as we explore their multimodal mechanisms in modulating neuroinflammation, promoting neurogenesis, and restoring cellular bioenergetics through the delivery of bioactive molecules and mitochondrial transfer. Recent advances in NSC-EV-based therapies for age-associated neurodegenerative diseases are highlighted, along with key challenges in EV production, preservation, and targeted delivery. Finally, we outline future directions for translating this promising approach into effective clinical treatments.

Keywords: extracellular vesicles (EVs); neural stem cells (NSCs); neurodegeneration; neuroinflammation; regenerative neuroimmunology

DOI: https://doi.org/10.1111/jnc.70170