bims-mitrat 2026-02-15 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2026–02–15
seven papers selected by
Gökhan Burçin Kubat, Başkent Üni̇versi̇tesi̇

Mitochondrial Transfer in the Tumor Microenvironment.
Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.
Simulating tumor mitochondrial energetics through engineering-style energy metrics.
Human umbilical mesenchymal stem cell-derived mitochondria transplantation suppresses sFLT-1 secretion by regulating calcineurin-NFAT-dependent pathways in angiotensin II-induced preeclampsia rats.
"Tumor-to-endothelium mitochondrial transfer licenses endothelial cells for CD8 + T cell recognition via mitochondrial neoantigen presentation".
Transient replication of bovine mitochondrial DNA and subsequent placental development in mouse embryos.
Plasma-derived mitochondria as a minimal manipulation alternative for attenuating inflammatory immune responses.

Cancer Sci. 2026 Feb 13.

Mitochondrial Transfer in the Tumor Microenvironment.

Ryo Omae, Takamasa Ishino, Yosuke Togashi.

  Mitochondria are not merely energy-producing organelles but also regulate metabolism, apoptosis, and inflammation. Recent studies have reported that mitochondria can be transferred between cells, and accumulating evidence suggests that this phenomenon is functionally relevant in the tumor context. Mitochondrial transfer is mediated by multiple routes such as tunneling nanotubes and extracellular vesicles. These pathways are regulated by Miro1/2, connexin 43, ICAM-1, VCAM-1, and intracellular reactive oxygen species. Within the tumor microenvironment, mitochondrial transfer from surrounding cells to tumor cells may serve as a mechanism by which tumor cells adapt to hostile metabolic conditions and evade therapeutic pressure. Furthermore, mitochondrial transfer from tumor cells to T cells in the tumor microenvironment reportedly impairs antitumor immunity. Based on these findings, novel therapeutic strategies targeting mitochondrial transfer are under investigation. Future challenges include the development of specific and safe methods to manipulate mitochondrial transfer in vivo. Understanding mitochondrial transfer and its regulation may offer new avenues to overcome resistance and improve cancer outcomes.

Keywords:  antitumor immunity; cell‐to‐cell interaction; mitochondria; mitochondrial transfer; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.70342
Blood Cancer Discov. 2026 Feb 10. OF1-OF13

Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.

Yutang Li, Xinting Hu, Xiangxiang Zhou.

Mitochondria regulate critical cellular processes beyond energy production, including organelle quality control, programmed cell death, and intercellular and interorganellar communication. In hematologic malignancies, mitochondria undergo adaptations through mechanisms including genetic mutations, metabolic reprogramming, mitochondrial transfer, fusion, and mitophagy. These alterations create heterogeneity, contribute to therapeutic resistance, and can also reshape the tumor microenvironment to promote progression. Collectively, these findings suggest that mitochondria represent a promising frontier in next-generation therapeutics, with emerging strategies such as mitochondrial-targeted small molecules and mitochondrial transplantation holding significant therapeutic potential.
SIGNIFICANCE: In this review, we summarize the functions of mitochondria beyond energy production and highlight the heterogeneity of mitochondrial functional adaptations in hematologic malignancies, as well as the vital role of mitochondrial alterations in reshaping the tumor microenvironment. Understanding these changes is critical to deciphering the pathophysiology of hematologic malignancies.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0338
Biosystems. 2026 Feb 05. pii: S0303-2647(26)00029-8. [Epub ahead of print]262 105719

Simulating tumor mitochondrial energetics through engineering-style energy metrics.

Arturo Tozzi.

  Cancer progression is linked to alterations in cellular energetics, where malignant cells reprogram their metabolism to sustain proliferation, resist stress and adapt to nutrient limitations. Recent work has shown that tumors actively remodel their microenvironment by acquiring functional mitochondria from surrounding stromal or immune cells. Mitochondrial transfer enhances tumor bioenergetics while simultaneously depleting immune cells of metabolic competence, thereby reinforcing both tumor growth and immune evasion. The energetic consequences in terms of throughput, efficiency and stored energy of these exchanges are not captured by conventional assays focused on oxygen consumption or glycolytic flux. We introduce a simulation-based framework for theoretical analysis of mitochondrial energetics that adapts engineering-style energy metrics to mitochondrial biology. Three theoretical, model-defined bioenergetic metrics are introduced: mitochondrial power density, expressing ATP production per unit mitochondrial volume; mitochondrial surface power density, relating ATP production to inner membrane area; and mitochondrial energy density, quantifying stored chemical free energy per unit volume. Using controlled in silico simulations of tumor and immune cell populations before and after modeled mitochondrial transfer, we examine how these descriptors vary under explicit simulation assumptions. Within our simulation framework, results indicate model-predicted differences between cell populations, with tumor-associated mitochondria occupying higher energetic throughput and immune-associated mitochondria exhibiting complementary reductions. Although exploratory and hypothesis-generating rather than validated biomarkers or clinical tools, our metrics provide a quantitative physical framework that may inform experimental studies of mitochondrial transfer and its energetic consequences, including efforts to disrupt pathogenic transfer and restore metabolic competence in immune cells.

Keywords:  Cristae morphology; Immune evasion; Metabolic profiling; Oxidative phosphorylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biosystems.2026.105719
Stem Cell Res Ther. 2026 Feb 13.

Human umbilical mesenchymal stem cell-derived mitochondria transplantation suppresses sFLT-1 secretion by regulating calcineurin-NFAT-dependent pathways in angiotensin II-induced preeclampsia rats.

Hui Xing Cui, Jun Xian Liu, Young Cheol Kang, Kyuboem Han, Hong Kyu Lee, Chun-Hyung Kim, Yin Hua Zhang.

   BACKGROUND: Mitochondrial transplantation (Mito-T) is a novel therapeutic strategy for ischaemic cardiovascular diseases. This study aimed to test the efficacy of human umbilical mesenchymal stem cell-derived mitochondrial transplantation (Mito-T) on preeclampsia (PE).
METHODS: PE was induced in Sprague-Dawley pregnant rats by infusing angiotensin II (Ang II) starting on gestation day 8 (GD 8). Mito-T (100 μg/μl) was injected via the jugular vein on GD 14.
RESULTS: On GD 20, PE rats exhibited high blood pressure, kidney and placental vascular abnormalities, reduced placental and foetal weights, foetal crown-rump lengths. Mito-T was predominantly distributed in the kidneys, uterus, and placenta of PE rats. Mito-T reversed clinical manifestations of PE, restored placental vascular abnormalities, and reduced serum sFLT-1 levels and the sFLT-1/PlGF ratio. In placental mitochondria, Mito-T increased protein levels of complexes (I‒V), improved mitochondrial membrane potential, ATP synthase, citrate synthase activities, and biogenesis markers (PGC-1α, TFAM, and NRF1), and reduced reactive oxygen species production. Mito-T increased mitochondrial fusion proteins (OPA1, MFN1, and MFN2) in the placenta, whereas fission (DRP1 and FIS1) and mitophagy (PINK, BNIP3, BNIP3L, and FUNDC1) proteins were reduced. In placental tissue, primary trophoblast cells, and the Bewo cell line, Mito-T reduced the mRNA and protein levels of sFLT-1 and attenuated the calcineurin-NFAT pathways elevated by PE or Ang II.
CONCLUSIONS: This study demonstrates that Mito-T reverses the pathological phenotypes of PE rats by improving placental mitochondrial activity and suppressing trophoblast-derived sFLT-1 production. These findings provide proof-of-concept evidence that Mito-T could serve as a potential therapeutic strategy for reducing maternal and foetal risks in patients with PE.

Keywords:  Calcineurin-NFAT-dependent pathways; Human umbilical mesenchymal stem cell; Mitochondrial transplantation; PlGF; Preeclampsia; ROS; Trophoblast cells; sFlt-1; sFlt-1/PlGF

DOI:  https://doi.org/10.1186/s13287-026-04930-9
bioRxiv. 2026 Feb 02. pii: 2026.01.30.702567. [Epub ahead of print]

"Tumor-to-endothelium mitochondrial transfer licenses endothelial cells for CD8 + T cell recognition via mitochondrial neoantigen presentation".

Francesca Costabile, Pierini Stefano, Renzo Perales-Linares, Nektaria Leli, Adham Bear, Cameron J Koch, Beatriz M Carreno, Michael Lotze, Lerry Singh, Marny Falck, Andrea Facciabene.

Renal cell carcinoma (RCC) frequently exhibits resistance to immune checkpoint blockade, highlighting the need for strategies that enhance tumor-specific T cell priming and improve immune access to the tumor microenvironment. Here we show that vaccination targeting tumor-associated mitochondrial antigens (TAMAs), derived from tumor-specific mitochondrial DNA (mtDNA) missense mutations, synergizes with PD-1/PD-L1 blockade to overcome checkpoint refractoriness in the RENCA RCC model. TAMAs vaccination elicits antigen-specific T cell responses, increases intratumoral CD8 + T cell infiltration, and reduces immunosuppressive myeloid populations, resulting in delayed tumor progression and improved survival when combined with checkpoint inhibition. In parallel, TAMAs + checkpoint blockade induces vascular remodeling characterized by increased pericyte coverage, reduced vascular leakage, improved perfusion and reduced hypoxia. Mechanistically, vascular remodeling is driven by CD8 + T cell-dependent, IFN γ -associated immune activity and is associated with endothelial apoptosis and diminished intratumoral CD31 signal. We further identify tumor-to-endothelium mitochondrial transfer as a mechanism linking mitochondrial neoantigens to the tumor vascular compartment: tumor-derived mitochondria enter human and mouse endothelial cells in vitro and in vivo , and tumor-associated mtDNA mutations are detectable in endothelial fractions from murine tumors and human RCC specimens. Human endothelial cells can present mitochondrial neoantigens via MHC class I and become targets of TAMAs-specific CD8 + T cell cytotoxicity, including following mitochondrial acquisition from tumor cells. Together, these findings establish mitochondrial neoantigen immunity as a tractable approach to enhance checkpoint responses and reveal mitochondrial transfer as an antigenic bridge that expands immune targeting to the tumor vasculature.

DOI: https://doi.org/10.64898/2026.01.30.702567
Biochem Biophys Res Commun. 2026 Feb 09. pii: S0006-291X(26)00195-6. [Epub ahead of print]807 153431

Transient replication of bovine mitochondrial DNA and subsequent placental development in mouse embryos.

Masaya Komatsu, Hanako Bai, Masashi Takahashi, Manabu Kawahara.

  Mitochondrial DNA (mtDNA) replication during early development is believed to depend on species-specific coordination between the mitochondrial and nuclear genomes. Here, we examined the fate and developmental consequences of bovine mtDNA introduced into mouse embryos using an interspecies mitochondrial transplantation model. Bovine mtDNA exhibited transient amplification during mouse preimplantation development, but declined at the blastocyst stage. Nevertheless, bovine mtDNA persisted in both embryonic and extraembryonic tissues after implantation. Using tetraploid complementation, we further demonstrated that mtB-M embryos developed enlarged placentas with expansion of the spongiotrophoblast layer, accompanied by upregulation of the Sfmbt2-miR-466 m axis. These findings highlight partial engagement of host replication machinery by heterologous mtDNA and species-specific constraints on mtDNA replication in shaping placental development in vivo.

Keywords:  Interspecies mitochondrial transplantation; Mito-nuclear incompatibility; Mitochondrial DNA replication; Sfmbt2–miR-466 m axis; Spongiotrophoblast expansion

DOI:  https://doi.org/10.1016/j.bbrc.2026.153431
Regen Biomater. 2026 ;13 rbaf132

Plasma-derived mitochondria as a minimal manipulation alternative for attenuating inflammatory immune responses.

Seong-Hoon Kim, Eun-Seo Back, Ikhyun Lim, Mina Lim, Mi Jin Kim, Kyunghoon Min, Chang-Koo Yun, Yong-Soo Choi.

  Platelet-rich plasma (PRP) has long been used to promote tissue repair through its content of cytokines, growth factors and platelet-derived mitochondria (PLT-mito). While effective, PRP often triggers an early M1-type inflammatory response that may worsen symptoms in chronic inflammatory conditions and limit its clinical utility. Harvesting functional PLT-mito usually requires platelet activation or mechanical disruption, which can exceed minimal manipulation thresholds under regulatory guidelines. In contrast, plasma-derived mitochondria (p-mito) provide an alternative, as they are naturally present in circulating plasma and can be obtained by simple centrifugation without activation or cell disruption. In this study, we compared the effects of platelets, PLT-mito, platelet releasate and p-mito on macrophage polarization and fibroblast repair assays using THP-1 and HDF models. Macrophage polarization was quantified at the RNA level by PCR of M1-associated (CD80, CD86) and M2-associated (CD163, CD206) surface-marker transcripts after each treatment. Platelets and platelet releasate predominantly induced M1-like polarization, whereas both PLT-mito and p-mito promoted an M2 phenotype. Notably, p-mito achieved M2 induction comparable to PLT-mito without requiring prior activation or manipulation. In a fibroblast scratch migration assay, p-mito enhanced cell migration and proliferation, replicating the pro-reparative effects of platelets. These findings suggest that p-mito are a functionally competent, cell-free therapeutic modality capable of modulating macrophage phenotypes without triggering early inflammatory priming. This minimally manipulated, clinically accessible mitochondrial therapeutic can be prepared and applied in a manner similar to PRP, with the potential to reduce early pro-inflammatory responses.

Keywords:  inflammation modulation; macrophage polarization; minimal manipulation; plasma-derived mitochondria; platelet-derived mitochondria

DOI:  https://doi.org/10.1093/rb/rbaf132