bims-mitrat 2026-06-21 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2026–06–21
six papers selected by
Gökhan Burçin Kubat, Başkent Üni̇versi̇tesi̇

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
Block, clear, and boost: a novel therapeutic framework for targeting intercellular mitochondrial transfer in Cancer immunotherapy.
CAV1-dependent mitochondrial transfer from hucMSCs reprograms epithelial lipid metabolism to relieve pulmonary fibrosis.
Enhanced functional mitochondrial donation through glucose-responsive antioxidant microcarrier-engineered native-like MSCs accelerates diabetic wound healing.
Mesenchymal Stromal Cell-Derived Extracellular Vesicles Mediate Mitochondrial Delivery in Injury: Mechanistic Insights, Evidentiary Tiers, and Translational Challenges.

Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.

Amandine Grimm, Undine Lang, Anne Eckert.

  Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.

Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes

DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
Front Immunol. 2026 ;17 1871148

Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.

Zhenyuan Xu, Qingli Zhou, Jifei Miao.

  Intercellular mitochondrial transfer has emerged as a significant mode of communication within the tumor microenvironment (TME). We propose that this process operates as a stress-adaptive organelle economy, redistributing three biologically decisive assets (respiratory competence, redox tolerance, and stress history) among tumor, immune, and stromal cells according to local metabolic asymmetry. Cancer cells acquire healthy mitochondria from stromal and immune populations, thereby restoring oxidative phosphorylation, expanding metabolic plasticity, and driving chemoresistance. Tumor cells also engage in outward transfer that is recipient-selective. Damaged mitochondria may be exported to CD8+ T cells and fibroblasts, corrupting effector function and reprogramming the stroma, whereas functional mitochondria may be delivered to pro-tumor immune populations such as M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells to sustain their immunosuppressive activity. Functional mitochondria therefore play a dual role in tumorigenesis. The consequences for antitumor immunity depend on donor identity, cargo quality, and recipient lineage rather than on transfer itself. The principal transport routes are tunneling nanotubes, extracellular vesicles, and cell fusion, but biological outcome is ultimately governed by a post-transfer fate checkpoint involving PINK1/Parkin-mediated mitophagy and USP30-facilitated retention. Therapeutically, the goal is not to block or enhance transfer globally but to achieve context-selective modulation within an inherently bidirectional system.

Keywords:  cancer plasticity; extracellular vesicles; mitochondrial transfer; t cell exhaustion; tumor microenvironment; tunneling nanotubes

DOI:  https://doi.org/10.3389/fimmu.2026.1871148
Int Immunopharmacol. 2026 Jun 16. pii: S1567-5769(26)00873-8. [Epub ahead of print]185 117027

Block, clear, and boost: a novel therapeutic framework for targeting intercellular mitochondrial transfer in Cancer immunotherapy.

Ruoyan Liu, Yang Yang, Zhening Wang, Zhuopeng Hu, Lei Yang, Rui Guo, Hong Wang.

Intercellular mitochondrial transfer (IMT) is emerging as a critical regulator of the tumor microenvironment, reshaping bioenergetics, signaling, and therapeutic responsiveness across the tumor-immune interface. Mitochondrial material can be exchanged within the tumor microenvironment (TME) through multiple routes, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction-associated exchange, and cell-cell fusion. The outcome of this exchange depends strongly on the quality of the transferred mitochondrial material: delivery of metabolically competent mitochondria may restore oxidative phosphorylation and effector function in T cells, whereas transfer of damaged mitochondrial cargo may amplify oxidative stress and promote terminal dysfunction. Mitochondrial quality-control mechanisms, including the PINK1-Parkin pathway and USP30-regulated deubiquitination, may critically influence how recipient cells process transferred mitochondrial material. Beyond adaptive immunity, IMT has also been implicated in innate immune compartments, including macrophages, natural killer cells, and dendritic cells. More broadly, cancer cells can acquire mitochondrial support from non-malignant partners, including neurons, adipose-derived stem cells, and endothelial cells, thereby enhancing metabolic flexibility, drug resistance, and metastatic potential in selected contexts. Based on these mechanisms, this review proposes "Block, Clear, and Boost" as a hypothesis-generating framework for organizing future studies of IMT modulation in cancer immunotherapy. The three conceptual arms refer to blocking harmful transfer, clearing damaged mitochondrial cargo, and boosting immune cells through metabolic augmentation or engineered mitochondrial donation. Importantly, this framework has not been clinically validated, and its therapeutic relevance remains to be tested in route-specific, cell-type-specific, and prospectively designed studies. To support future translational development, we discuss candidate biomarkers for patient stratification, including host mtDNA haplogroups, somatic tumor signatures (e.g., Mitochondrial Pathway Signature, MitoPS), and circulating IMT proxies. Finally, we outline challenges and future directions for evaluating IMT modulation alongside existing immunotherapies, including immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs).

DOI: https://doi.org/10.1016/j.intimp.2026.117027
Stem Cell Res Ther. 2026 Jun 19.

CAV1-dependent mitochondrial transfer from hucMSCs reprograms epithelial lipid metabolism to relieve pulmonary fibrosis.

Ye Shao, Jinjin Zhang, Hanchen Liu, Yujie Wang, Bo Liu, Xinglong Yuan, Mengqi Jiang, Changjun Lv, Songzi Zhang, Xiaodong Song, Hongbo Li.

   BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by persistent epithelial injury accompanied by mitochondrial dysfunction. Although mesenchymal stem cells (MSCs) can restore epithelial function by donating mitochondria to damaged cells, the molecular mechanisms driving this process remain unclear. In this study, we demonstrate that caveolin-1 (CAV1) enhances mitochondrial transfer from human umbilical-cord-derived MSCs (hucMSCs) to injured epithelial cells.
METHODS: In vitro and in vivo bleomycin-induced models were used to evaluate mitochondrial transfer from hucMSCs to alveolar epithelial cells. Confocal microscopy and intravital lung imaging visualized mitochondrial transfer, while flow cytometry quantified transfer efficiency. Proteomic profiling, mitochondrial functional assays, and lipid analyses were conducted to explore CAV1-associated mechanisms and metabolic outcomes.
RESULTS: hucMSC treatment restored mitochondrial membrane potential, ATP production, and epithelial cell viability while reducing reactive oxygen species in injured MLE-12 cells. Proteomic analysis showed significant upregulation of CAV1 in hucMSCs cocultured with injured epithelial cells. In the same dataset, differentially expressed proteins were enriched in pathways related to cytoskeletal remodeling and vesicular transport, supporting a role for hucMSC membrane and trafficking dynamics in mitochondrial delivery. Functional validation confirmed that CAV1 overexpression markedly enhanced mitochondrial transfer and restored mitochondrial function, whereas CAV1 knockdown impaired both transfer efficiency and therapeutic outcomes. Mechanistically, transferred mitochondria promoted mitochondria-lipid droplet tethering, boosted fatty acid β-oxidation, and reduced lipid accumulation. CAV1-overexpressing hucMSCs alleviated alveolar epithelial injury and attenuated pulmonary fibrosis.
CONCLUSIONS: Our findings identify CAV1 as a crucial mediator of hucMSC-mediated mitochondrial transfer, which enhances epithelial repair through mitochondrial donation and metabolic reprogramming. These insights provide a mechanistic foundation for optimizing stem cell-based therapies in pulmonary fibrosis.

Keywords:  CAV1; Lipid metabolism; Mitochondrial transfer; Pulmonary fibrosis; hucMSCs

DOI:  https://doi.org/10.1186/s13287-026-05116-z
Mater Today Bio. 2026 Jun;38 103286

Enhanced functional mitochondrial donation through glucose-responsive antioxidant microcarrier-engineered native-like MSCs accelerates diabetic wound healing.

Xiaoxue Yang, Lin Ma, Anqi Liu, Peisheng Liu, Xinyue Cai, Siyuan Fan, Hao Guo, Kun Xuan, Xiaoyao Huang.

  Diabetes impairs wound healing due to hyperglycemia-induced vascular dysfunction. This condition triggers mitochondrial impairment, leading to ferroptosis in endothelial cells. While mesenchymal stromal cells (MSCs) can promote tissue repair through intercellular mitochondrial transfer, strategies to enhance their mitochondrial-donating capacity under hyperglycemic conditions remain underdeveloped. Mesenchymal condensation endows MSCs with enhanced regenerative potential and greater mitochondrial functionality. Microcarrier-based three-dimensional (3D) dynamic culture systems mimicking this process offer a promising strategy. However, effectively shielding donor MSCs from hyperglycemia-induced oxidative stress remains a key challenge in microcarrier design. Here, we engineered a glucose-responsive antioxidant biomaterial-based 3D dynamic culture system using chitosan-formylphenylboronic acid (CS-FPBA) microcarriers combined with stem cells from human exfoliated deciduous teeth (SHED) to generate native-like SHED (N-SHED). This system provides a protective niche for transplanted SHED through glucose-triggered antioxidant microcarrier degradation while simultaneously enhancing mitochondrial function and intercellular transfer. Consequently, N-SHED attenuated endothelial ferroptosis, promoted angiogenesis, and accelerated diabetic wound healing in vivo. This study presents a native-like cell culture platform that amplifies the therapeutic efficacy of MSCs by enhancing their mitochondrial-donating capacity. With strong translational potential, this strategy not only advances MSCs-based therapy for diabetic wounds but also offers a novel framework for mitochondrial-targeted regenerative medicine.

Keywords:  Diabetic wound healing; Ferroptosis; Glucose-responsive microcarrier; Mitochondrial transfer; Stem cells from human exfoliated deciduous teeth; Three-dimensional dynamic culture system

DOI:  https://doi.org/10.1016/j.mtbio.2026.103286
Stem Cell Rev Rep. 2026 Jun 17.

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Mediate Mitochondrial Delivery in Injury: Mechanistic Insights, Evidentiary Tiers, and Translational Challenges.

Tingkun Ma, Yuan He, Jincui Yang, Peng Luo, Qiyi Shen, Junjie Yang, Ding Xu, Xiao Li, Chunchu Deng, Kelu Li, Biao Chen, Yulong Shi.

  While mesenchymal stromal cell (MSC)-derived extracellular vesicles (MSC-EVs) offer a safer, cell-free alternative to stem cell transplantation, their specific role in rescuing recipient cell mitochondrial networks requires precise definition. This review clarifies that scientific landscape by systematically partitioning MSC-EV-mediated mitochondrial delivery into three rigorous, evidence-based categories: (i) the horizontal transfer of intact, bioenergetically active mitochondria, (ii) the lateral delivery of sub-organellar components such as mitochondrial DNA (mtDNA) and transcriptional proteins (e.g., TFAM), and (iii) indirect protective signaling that rejuvenates endogenous networks. Effectively integrated cargo within MSC-EV has been reported to restore mitochondrial membrane potential, contributing to the stabilization of electron transport chain complexes (I-IV), the reactive oxygen species (ROS) balance, and the tricarboxylic acid (TCA) cycle and NAD + /NADH balance to reverse bioenergetic collapse. Across diverse myocardial, pulmonary, hepatic, renal, and neurological injury models, this EV-associated delivery is associated with dampening of hyper-inflammation, enhances macrophage phagocytosis, and supports tissue barrier regeneration. Nevertheless, critical translational barriers remain, including significant EV heterogeneity, a lack of standardized high-purity isolation protocols in line with MISEV (Minimal Information for Studies of Extracellular Vesicles) guidelines, and unverified oncologic risks such as supporting tumor progression or chemoresistance through unintended metabolic rescue. In conclusion, large-scale clinical adoption requires prioritized, well-designed human trials with rigorous cargo characterization to firmly establish long-term safety, durability, and oncologic security.

Keywords:  Extracellular vesicle; Mesenchymal stromal cell; Mitochondrial delivery; Tissue injury

DOI:  https://doi.org/10.1007/s12015-026-11170-0