bims-mitrat 2025-11-23 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–11–23
seven papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondria transplantation mitigates attenuation of muscle fiber regeneration by evoked contractions.
Retrograde mitochondrial transport regulates mitochondrial biogenesis in zebrafish neurons.
Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells.
Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.
Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
Mitochondrial transfer from human embryonic stem cell-derived mature cardiomyocytes to mesenchymal stem cells.
Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.

Am J Physiol Cell Physiol. 2025 Nov 19.

Mitochondria transplantation mitigates attenuation of muscle fiber regeneration by evoked contractions.

Stephen E Alway, Hector G Paez, Peter J Ferrandi, Christopher R Pitzer, Jessica L Halle, Mohammad Moshahid Khan, Junaith S Mohamed, Michael R Deschenes, James A Carson.

  Rest is generally required for full muscle regeneration after an injury; however, rehabilitative activity is often used after injury to attempt a faster recovery. While rehabilitative activity can enhance muscle regeneration, there is also a risk that returning to vigorous muscle contractions too early after sustaining an injury, could reinjure the muscle, and negatively impact full muscle regeneration. It is not known whether MT added to rehabilitative muscle activity would speed regeneration of muscle morphology more rapidly than resting during the recovery period. Therefore, submaximal electrically evoked isometric contractions (EC) were given to injured muscles of MT treated mice, to test the hypothesis that MT would attenuate the negative regenerative effects of EC and improve the restoration of muscle mass and morphology after muscle injury. Cardiotoxin (CTX) was injected into the tibialis anterior (TA) muscle of one limb of C57BL/6 mice at 8-12 weeks of age to induce muscle injury. Systemic delivery MT or PBS was administered to the mice 48 h after injury. The TA received EC at 40Hz every other day for up to 14-days after CTX injury. While EC-induced mechanical injury slowed muscle repair, muscle fiber regeneration and nuclear domain size was improved by MT. The percentage of collagen and other non-contractile tissue was elevated in CTX-injured and EC treated muscles; however, MT reduced fibrosis/non-contractile tissue deposition in regenerating muscles. Our results provide evidence that systemic mitochondria delivery can improve muscle repair and can attenuate contraction-suppressed muscle fiber regeneration during recovery after injury.

Keywords:  fibrosis; mitochondria; muscle fiber types; muscle injury; regeneration

DOI:  https://doi.org/10.1152/ajpcell.00744.2025
bioRxiv. 2025 Oct 01. pii: 2025.09.29.679307. [Epub ahead of print]

Retrograde mitochondrial transport regulates mitochondrial biogenesis in zebrafish neurons.

Angelica E Lang, Chris Stein, Catherine M Drerup.

To maintain a healthy mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because the majority of mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires nuclear sensing of mitochondrial population health and function. This can be a challenge in a large, compartmentalized cell like a neuron in which a large portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with mitochondrial gene expression. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.

DOI: https://doi.org/10.1101/2025.09.29.679307
Trends Cell Biol. 2025 Nov 15. pii: S0962-8924(25)00245-4. [Epub ahead of print]

Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells.

Takamasa Ishino, Yu Inutsuka, Hideki Ikeda, Yosuke Togashi.

  Mitochondria are organelles that are essential for their multiple roles in cell biology, including energy metabolism. Accumulating evidence has revealed that intercellular mitochondrial transfer occurs within the tumor microenvironment (TME). The mitochondrial transfer among the TME components can profoundly affect tumor progression, immune surveillance, and stromal remodeling. Importantly, cancer cells function not only as recipients but also as donors of mitochondria, underscoring the bidirectional nature of this process. This review summarizes the multifaceted roles of mitochondria in cancer cells, immune cells, and stromal cells, with particular emphasis on emerging insights into mitochondrial transfer. In addition, the current implications of mitochondria-targeting therapies and future challenges in this evolving field are highlighted.

Keywords:  antitumor immunity; cancer; mitochondria; mitochondrial transfer

DOI:  https://doi.org/10.1016/j.tcb.2025.10.004
BMB Rep. 2025 Nov 20. pii: 6418. [Epub ahead of print]

Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.

Dohee Kim, Seo-Eun Lee, JuHyuen Cha, Jun Ho Lee, Young Cheol Kang, Sang-Yeon Lee.

This study examined therapeutic potential of mitochondrial transplantation using PN-101, a mitochondria preparation derived from human umbilical cord mesenchymal stem cells (UCMSCs), to address SSBP1-related mitochondrial DNA (mtDNA) depletion syndrome. Patient-derived fibroblasts harboring a heterozygous SSBP1 mutation (c.272G＞A:p.Arg91Gln) were treated with PN-101. Its successful uptake and integration into these cells were confirmed. Subsequent analyses revealed that PN-101 treatment significantly increased mtDNA copy numbers in a time- and dose-dependent manner, elevated the expression of key oxidative phosphorylation proteins, and enhanced overall mitochondrial bioenergetics. Taken together, these results provide strong evidence that mitochondrial transplantation holds promise as a therapeutic strategy for primary mitochondrial diseases, including those involving SSBP1 mutations.
Int Rev Immunol. 2025 Nov 17. 1-30

Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.

Thao Hoang Nhu Le, Van Thi Tuong Nguyen.

  Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.

Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer

DOI:  https://doi.org/10.1080/08830185.2025.2577986
BMB Rep. 2025 Nov 20. pii: 6458. [Epub ahead of print]

Mitochondrial transfer from human embryonic stem cell-derived mature cardiomyocytes to mesenchymal stem cells.

Ye Seul Jeong, Dasol Kim, Yoon Ji Jung, Jung Won Yoon, Yong Seong Kwon, Seong-Jang Kim, Jae Ho Kim.

Mitochondria are crucial for energy metabolism and their dysfunction is implicated in the development of various human diseases. Direct mitochondrial transplantation has shown potential in reversing mitochondrial dysfunction in recipient cells. Mesenchymal stem cells (MSCs) present a promising approach as donor cells for such transplantation. We have previously demonstrated that tomatidine, a natural steroidal alkaloid, promotes the differentiation of human embryonic stem cells (hESCs) into mature cardiomyocytes by enhancing mitochondrial quantity and function. In this study, we assessed the capacity of hESCderived cardiomyocytes (hESC-CMs) and MSCs as donor cells for mitochondrial transplantation. Mitochondria were extracted from MSCs, immature hESC-CMs, and tomatidine-treated mature hESC-CMs. Treating MSCs with mitochondria derived from mature hESC-CMs led to a marked increase in mitochondrial protein levels, such as COX IV and MIC60, in the recipient MSCs, in comparison to those receiving mitochondria from immature hESC-CMs or MSCs. Transplantation of mature hESC-CM-derived mitochondria significantly enhanced the proliferation of recipient MSCs. These findings indicate that mature hESC-CMs are highly effective as donor cells for mitochondrial transplantation in addressing mitochondrial dysfunction.
Cancer Res. 2025 Nov 17.

Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.

Maria Dubisova, Klara Bohacova, Zuzana Nahacka, Daniel Kraus, Jaromir Novak, Sarka Dvorakova, Petra Brisudova, Natalie Danesova, Saba Selvi, Mariia Hrysiuk, Berwini B Endaya, Panagiotis Botsios, Dan-Diem Thi Le, Monika Novotna, Sona Vodenkova, Jaroslav Truksa, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Stepana Boukalova, Michael V Berridge, Renata Zobalova, Jiri Neuzil.

Cancer cells with severe defects in mitochondrial DNA (mtDNA) can import mitochondria via horizontal mitochondrial transfer (HMT) to restore respiration. Mitochondrial respiration is necessary for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme of the inner mitochondrial membrane that catalyzes the fourth step of de novo pyrimidine synthesis. Here, we investigated the role of de novo synthesis of pyrimidines in driving tumor growth in mtDNA-deficient (ρ0) cells. While ρ0 cells grafted in mice readily acquired mtDNA, this process was delayed in cells transfected with alternative oxidase (AOX), which combines the functions of mitochondrial respiratory complexes III and IV. The ρ0 AOX cells were glycolytic but maintained normal DHODH activity and pyrimidine production. Deletion of DHODH in a panel of tumor cells completely blocked or delayed tumor growth. The grafted ρ0 cells rapidly recruited tumor-promoting/stabilizing cells of the innate immune system, including pro-tumor M2 macrophages, neutrophils, eosinophils, and mesenchymal stromal cells (MSCs). The ρ0 cells recruited MSCs early after grafting, which were potential mitochondrial donors. Grafting MSCs together with ρ0 cancer cells into mice resulted in mitochondrial transfer from MSCs to cancer cells. Overall, these findings indicate that cancer cells with compromised mitochondrial function readily acquire mtDNA from other cells in the tumor microenvironment to restore DHODH-dependent respiration and de novo pyrimidine synthesis. The inhibition of tumor growth induced by blocking DHODH supports targeting pyrimidine synthesis as a potential widely applicable therapeutic approach.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0737