bims-mitrat 2025-03-02 papers

Biomolecules. 2025 Jan 27. pii: 184. [Epub ahead of print]15(2):

Mitochondrial Transplantation in Animal Models of Psychiatric Disorders: A Novel Approach to Psychiatric Treatment.

Keiko Iwata, Masafumi Noguchi, Norihito Shintani.

Mitochondria are essential for brain function, and accumulating evidence from postmortem brain studies, neuroimaging, and basic research indicates mitochondrial impairments in patients with psychiatric disorders. Restoring mitochondrial function therefore represents a promising therapeutic strategy for these conditions. Mitochondrial transplantation, an innovative approach that uses functional mitochondria to repair damaged cells, has demonstrated efficacy through various delivery methods in cell, animal, and animal disease models. This review explores the critical link between mitochondria and psychiatric disorders and provides an overview of mitochondrial transplantation as a therapeutic intervention. It highlights recent advances in mitochondrial transplantation in animal models of psychiatric disorders, focusing on delivery methods, the timing of administration, and the integration of exogenous mitochondria into brain cells. The potential therapeutic effects and the mechanisms that underlie these effects are discussed. Additionally, this review evaluates the clinical relevance, challenges, and future strategies for the application of mitochondrial transplantation in the treatment of psychiatric disorders.

Keywords: brain functions; experimental disease models; mitochondrial transplantation; psychiatric disorders; therapeutic strategies

DOI: https://doi.org/10.3390/biom15020184

Mol Ther Nucleic Acids. 2025 Mar 11. 36(1): 102449

Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells.

Kyrie Wilson, Charles Holjencin, Hwaran Lee, Balasubramaniam Annamalai, Masaaki Ishii, Jeremy L Gilbert, Andrew Jakymiw, Bärbel Rohrer.

Gene therapy approaches for mitochondrial DNA (mtDNA)-associated damage/diseases have thus far been limited, and despite advancements in single gene therapy for mtDNA mutations and progress in mitochondrial transplantation, no method exists for restoring the entire mtDNA molecule in a clinically translatable manner. Here, we present for the first time a strategy to deliver an exogenous, fully intact, and healthy mtDNA template into cells to correct endogenous mtDNA mutations and deletions, with the potential to be developed into an efficient pan-therapy for inherited and/or acquired mtDNA disorders. More specifically, the novel therapeutic nanoparticle complex used in our study was generated by combining a cell-penetrating peptide (CPP) with purified mtDNA, in conjunction with a mitochondrial targeting reagent. The generated nanoparticle complexes were found to be taken up by cells and localized to mitochondria, with exogenous mtDNA retention/maintenance, along with mitochondrial RNA and protein production, observed in mitochondria-depleted ARPE-19 cells at least 4 weeks following a single treatment. These data demonstrate the feasibility of restoring mtDNA in cells via a CPP carrier, with the therapeutic potential to correct mtDNA damage independent of the number of gene mutations found within the mtDNA.

Keywords: MT: Delivery Strategies; age-related diseases; cell-penetrating peptide; mitochondria; mitochondrial DNA; mitochondrial transplantation; mtDNA; mtDNA gene therapy; mtDNA mutations; nucleic acid delivery

DOI: https://doi.org/10.1016/j.omtn.2025.102449

Stem Cell Res Ther. 2025 Feb 23. 16(1): 87

Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.

Hsin-Yi Tsai, Kuen-Jang Tsai, Deng-Chyang Wu, Yaw-Bin Huang, Ming-Wei Lin.

BACKGROUND: Gastric cancer is the malignant disease. The problems associated with cancer stemness and chemotherapy resistance in gastric cancer therapy remain unresolved. Glucose-regulated protein 78 (GRP78) is a biomarker of gastric cancer and modulates cancer stemness and chemoresistance. Previous studies have shown that mitochondrial transplantation from healthy cells is a promising method for treating various diseases and that the regulation of mitochondrial metabolism is crucial for modulating the stemness and chemoresistance of cancer cells. The aim of this study was to investigate the therapeutic effect of mitochondrial transplantation from normal gastric epithelial cells into gastric cancer and the associated mechanisms.
METHODS: The expression of cancer stemness markers, intracellular oxidative stress, or apoptotic-related proteins were evaluated via flow cytometry. Western blotting was used to investigate the molecular mechanism involved in MKN45 or AGS human gastric cancer cells after transplantation with human gastric epithelial mitochondria. The mitochondrial metabolic function of gastric cancer cells was determined via a Seahorse bioanalyzer, and extracellular lactate was evaluated via bioluminescent assay. The viability of 5-fluorouracil (5-FU)-treated gastric cancer cells was detected via a CCK-8 assay. Furthermore, a xenograft tumor animal study was performed to validate the therapeutic effects of human gastric epithelial mitochondrial transplantation in gastric cancer. Immunohistochemistry and Western blotting were then used to assess the expressions related to cancer stemness and mitochondrial metabolism-related proteins in tumor tissues.
RESULTS: Transplanting human gastric epithelial mitochondria downregulates gastric cancer mitochondrial biogenesis, glycolysis, GRP78-mediated cancer stemness, and increases oxidative stress, cell apoptosis under hypoxic conditions and chemosensitivity in response to 5-FU treatment. Moreover, the transplantation of epithelial mitochondria into gastric tumors inhibited the tumor growth in vivo tumor graft animal models. Therefore, mitochondrial transplantation can be considered for the treatment of gastric cancer.

Keywords: Apoptosis; Cancer stemness; Chemoresistance; GRP78; Gastric cancer; Metabolism; Mitochondrial transplantation

DOI: https://doi.org/10.1186/s13287-025-04223-7

J Clin Invest. 2025 Feb 27. pii: e189801. [Epub ahead of print]

Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation.

Chengjie Gao, Yitian Dai, Paul A Spezza, Paul Boasiako, Alice Tang, Giselle Rasquinha, Hui Zhong, Bojing Shao, Yunfeng Liu, Patricia A Shi, Cheryl A Lobo, Xiuli An, Anqi Guo, William B Mitchell, Deepa Manwani, Karina Yazdanbakhsh, Avital Mendelson.

Newly produced platelets acquire a low activation state but whether the megakaryocyte plays a role in this outcome has not been fully uncovered. Mesenchymal stem cells (MSCs) were previously shown to promote platelet production and lower platelet activation. We found healthy megakaryocytes transfer mitochondria to MSCs mediated by Connexin 43 (Cx43) gap junctions on MSCs, which leads to platelets at a low energetic state with increased LYN activation, characteristic of resting platelets. On the contrary, MSCs have a limited ability to transfer mitochondria to megakaryocytes. Sickle cell disease (SCD) is characterized by hemolytic anemia and results in heightened platelet activation, contributing to numerous disease complications. Platelets in SCD mice and human patient samples had a heightened energetic state with increased glycolysis. MSC exposure to heme in SCD led to decreased Cx43 expression and a reduced ability to uptake mitochondria from megakaryocytes. This prevented LYN activation in platelets and contributed to increased platelet activation at steady state. Altogether, our findings demonstrate an effect of hemolysis in the microenvironment leading to increased platelet activation in SCD. These findings have the potential to inspire new therapeutic targets to relieve thrombosis-related complications of SCD and other hemolytic conditions.

Keywords: Bone marrow; Hematology; Mouse stem cells; Platelets; Stem cells

DOI: https://doi.org/10.1172/JCI189801