bims-mitrat 2025-06-29 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–06–29
seven papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondrial Transplantation Reduces Injury and Improves Liver Function in a Porcine Model of Hemi-Hepatic Ischemia/reperfusion.
Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
There is no transfer of mitochondria from donor hematopoietic cells to recipient mesenchymal stromal cells after allogeneic hematopoietic stem cells transplantation in humans.
Nerve-to-cancer transfer of mitochondria during cancer metastasis.
"Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".
Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome.
Mitochondrial Transfer from Human Platelets to Rat Dental Pulp-Derived Fibroblasts in the 2D In Vitro System: Additional Implication in PRP Therapy.

Ann Surg. 2025 Jun 25.

Mitochondrial Transplantation Reduces Injury and Improves Liver Function in a Porcine Model of Hemi-Hepatic Ischemia/reperfusion.

Christian Hobeika, Avinash Naraiah Mukkala, Kun Wang, Nicola Sariye Pollmann, Sujani Ganesh, Francisco Calderon Novoa, Catherine Parmentier, Simon Qu, Ramadan Karrout, Cindy Lin, Emma Mizdrak, Mickaël Lesurtel, Nazia Selzner, Trevor Reichman, Oyedele Adeyi, Eno Hysi, Ori David Rotstein, Markus Selzner.

   OBJECTIVE: To assess mitochondrial transplantation (MitoTx) via portal vein infusion to reduce liver ischemia-reperfusion injury (I/R) in a survival porcine model.
SUMMARY BACKGROUND DATA: MitoTx has been shown to alleviate I/R injury in various organs.
METHODS: Male Yorkshire pigs (38±1 kg) were subjected to 2 hours of ischemia in the left hemi-liver (left portal-triad clamping), and at the beginning of reperfusion (marked as t=0h), animals received a 1-hour infusion of autologous mitochondria (MT, 6.71×109/kg) or saline (controls) via the portal vein. Liver tissue oxygen saturation (sO2) was assessed by photoacoustic imaging.
RESULTS: Twelve pigs (6 MitoTx vs. 6 controls) underwent 2-hour left hemi-liver I/R. All pigs recovered and were ambulatory at t=6h. MitoTx reduced peak AST levels at t=2h compared to controls (299.83±46.62 vs. 878.83±255.09 UI/L; P=0.049). At t=24h, MitoTx pigs had lowered necrosis area percentage (8.01±4.12 vs. 23.40±7.33%; P=0.08) in left livers- all right lobes had 0% necrotic area. MitoTx pigs had shorter prothrombin time, plateauing around t=8h (12.9±0.3 vs. 14.1±0.1s; P=0.003), faster lactate clearance (<2 mmol/L) from the blood (HR: 1.3, [1.1, 1.7]; P=0.003) and from the bile (HR: 1.4, [1.1, 1.7]; P=0.009) compared to controls. At t=6h, MitoTx pigs had decreased IL-6 (304±71 vs. 686±87 pg/mL; P=0.007). Photoacoustic imaging showed that MitoTx pigs had a smaller variation of sO2 from baseline in left livers compared to controls (at t=30min; -3.05±2.72 vs. -15.19±2.92%; P=0.016).
CONCLUSION: MitoTx reduces injury and improves liver function after prolonged liver I/R, showing promise for liver transplantation.

Keywords:  inflammation; large animal study; liver function; mitochondrial transplantation; porcine liver ischemia/reperfusion injury

DOI:  https://doi.org/10.1097/SLA.0000000000006817
Nature. 2025 Jun 25.

Neuronal transfer of mitochondria to tumour cells promotes cancer spread.

Anand K Singh, Yuan Pan.



Keywords:  Cancer; Medical research; Neuroscience

DOI:  https://doi.org/10.1038/d41586-025-01718-4
Hematol Transfus Cell Ther. 2025 Jun 18. pii: S2531-1379(25)00127-0. [Epub ahead of print]47(3): 103859

There is no transfer of mitochondria from donor hematopoietic cells to recipient mesenchymal stromal cells after allogeneic hematopoietic stem cells transplantation in humans.

Natalya Sats, Vadim Surin, Tatiana Abramova, Aleksandra Sadovskaya, Nataliya Petinati, Nikolay Kapranov, Ksenia Nikiforova, Nina Drize, Luisa Karaseva, Olga Pokrovskaya, Larisa Kuzmina, Elena Parovichnikova.

   INTRODUCTION: Multipotent mesenchymal stromal cells are progenitors of the bone marrow stromal microenvironment that support hematopoiesis. Mitochondria, which can be transferred between cells via nanotubes or extracellular vesicles, play a key role in the functions of mesenchymal stromal cells. In a murine model, donor hematopoietic stem and progenitor cells transfer functional mitochondria to bone marrow mesenchymal stromal cells of the recipient. The aim of this study was to find out whether such transfer occurs in humans after allogeneic hematopoietic stem cell transplantation.
METHODS: This study included nine patients with acute leukemia who received a reduced intensity conditioning regimen. Donor hematopoietic stem and progenitor cells mobilized into peripheral blood were the source of transplanted stem cells. Total DNA was isolated from bone marrow mesenchymal stromal cells of each patient before and after transplantation and their respective donors' leukocytes. A fragment of mitochondrial DNA including the full-length control region was sequenced. The mitochondrial DNA sequence of each patient's mesenchymal stromal cells was compared before and after the procedure and with the respective donor leukocytes.
RESULTS: Donor mitochondrial DNA was not detected in the mesenchymal stromal cells of any patient after transplantation even as trace amounts. Co-culturing donor leukocytes with intact and irradiated mesenchymal stromal cells in vitro did not lead to detection of donor mitochondrial DNA transfer.
CONCLUSION: The data show that there is no mitochondrial transfer from donor hematopoietic stem and progenitor cells to recipient mesenchymal stromal cells after transplantation. Thus, the results indicate that one cannot count on improved mesenchymal stromal cell metabolism due to mitochondrial transfer. It is necessary to look for other ways to restore the stromal microenvironment.

Keywords:  Hematopoietic stem cell transplantation; Mesenchymal stromal cells; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1016/j.htct.2025.103859
Nature. 2025 Jun 25.

Nerve-to-cancer transfer of mitochondria during cancer metastasis.

Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T Lin, William Hixson, Terry W Pierce, Joel F Andrews, Mikhail F Alexeyev, Yi Ding, Ping Bu, Fariba Behbod, Daniel Medina, Jeffrey T Chang, Gustavo Ayala, Simon Grelet.

The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.

DOI: https://doi.org/10.1038/s41586-025-09176-8
Free Radic Biol Med. 2025 Jun 24. pii: S0891-5849(25)00789-0. [Epub ahead of print]

"Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".

Quentin Perrier, Veronica Lisi, Kelsey Fisherwellman, Sandrine Lablanche, Amish Asthana, Giuseppe Orlando, Sophie Maiocchi.

  Mitochondrial and extracellular vesicles (EV) transplantation have emerged as promising therapeutic strategies targeting mitochondrial dysfunction, a central feature of numerous pathologies. This review synthesizes preclinical data on artificial mitochondrial and EV transfer, emphasizing their therapeutic potential and underlying mechanisms. A systematic analysis of 123 animal studies revealed consistent benefits across diverse models, including ischemia-reperfusion injury (IRI), neurological disorders, drug-induced toxicities, and sepsis. Mitochondrial transfer improved organ function, reduced inflammation and apoptosis, and enhanced survival. Mechanistic insights revealed restored bioenergetics, increased oxidative phosphorylation, redox balance through activation of specific pathways, and modulation of mitochondrial dynamics via fusion/fission proteins. Mitochondrial homeostasis was supported through elevated mitophagy and biogenesis, alongside the preservation of mitochondrial-associated membranes. EV demonstrated similar effects, offering a potentially more targeted therapeutic alternative. Although pre-clinical studies have demonstrated safety and feasibility, broader application is limited by variability in isolation methods, lack of mechanistic clarity, and minimal human data. Standardization and mechanistic validation are critical to advance clinical translation. This review underscores the therapeutic promise of mitochondrial and EV transfer while highlighting the need for continued research to refine these interventions and unlock their full potential in regenerative medicine.

Keywords:  Artificial Mitochondrial transfer; Extracellular vesicles; Microvesicles; Mitochondrial Transplantation; Pre-clinical data; Therapeutic; Treatment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.040
Exp Mol Med. 2025 Jun 24.

Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome.

Ye Seul Kim, Sukdong Yoo, Yoon Ji Jung, Jung Won Yoon, Yong Seong Kwon, Nayeon Lee, Chong Kun Cheon, Jae Ho Kim.

Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN, which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. Here we explored the possibility of using stem-cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem (iPS) cells from healthy individuals and from patients with BTHS and differentiated them into cardiomyocytes. The iPS-cell-differentiated cardiomyocytes (CMs) derived from patients with BTHS exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT and cTnI, and smaller cell size than normal iPS-cell-derived CMs. Multielectrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired and mitophagy was decreased in BTHS CMs compared with normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.

DOI: https://doi.org/10.1038/s12276-025-01472-7
Int J Mol Sci. 2025 Jun 08. pii: 5504. [Epub ahead of print]26(12):

Mitochondrial Transfer from Human Platelets to Rat Dental Pulp-Derived Fibroblasts in the 2D In Vitro System: Additional Implication in PRP Therapy.

Koji Nishiyama, Tomoni Kasahara, Hideo Kawabata, Tetsuhiro Tsujino, Yutaka Kitamura, Taisuke Watanabe, Masayuki Nakamura, Tomoharu Mochizuki, Takashi Ushiki, Tomoyuki Kawase.

  Platelet mitochondria have recently been increasingly considered "co-principal" along with platelet growth factors to facilitate tissue regeneration in platelet-rich plasma therapy cooperatively. To develop a convenient method to test this potential, we examined mitochondrial transfer using a simple two-dimensional culture system. Living human platelets were prepared from PRP obtained from 12 non-smoking healthy male adults (age: 28-63 years) and suspended in medium. Platelet lysates were prepared from sonicated platelet suspensions in PBS. After treatment with ultraviolet-C irradiation, a mitochondrial respiration inhibitor, or a synchronized culture reagent, rat dental pulp-derived fibroblasts (RPC-C2A) were co-cultured with platelets or platelet lysates for 24 h. Mitochondrial transfer was evaluated by visualization using a fluorescent dye for mitochondria or an antibody against human mitochondria. Ultraviolet-C-irradiated cells substantially lost their viability, and treatment with living platelets, but not platelet lysates, significantly rescued the damaged fibroblasts. Fibroblast mitochondria appeared to increase after co-culture with resting platelets. Although more microparticles existed around the platelets on the fibroblast surface, the activated platelets did not show significant increases in any parameters of mitochondrial transfer. This simple co-culture system demonstrated mitochondrial transfer between xenogeneic cells, and this phenomenon should be considered as an additional implication in PRP therapy.

Keywords:  fibroblasts; in vitro; mitochondria; platelet-rich plasma; platelets; transfer

DOI:  https://doi.org/10.3390/ijms26125504