bims-mitrat 2026-11-01 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2026–11–01
fourteen papers selected by
Gökhan Burçin Kubat, Başkent Üni̇versi̇tesi̇

Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
Donor-Cell Senescence Redirects PINK1-Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3-Stabilized HSPA9.
Intercellular Mitochondria Transfer as a Bioenergetic Rescue Mechanism in CNS Injury: Mechanisms, Therapeutic Potential, and Translational Barriers.
Encapsulated mitochondrial transplantation: Advancing organelle therapeutics.
Mitochondria-rich cytochalasomes as an intravenously deliverable vesicle platform for ischemic heart disease.
Effects of Stem Cell-Derived Mitochondrial Transfer on H2O2-Induced Oxidative Stress in COV434 Granulosa Cells.
Photosynthetic chimeric stem cells function as mitochondrial batteries.
Mitochondrial transplantation as a therapeutic strategy: From energy replacement to metabolic and immune reprogramming.
Mitochondrial acquisition after the Asgard revolution: Reconstructing eukaryogenesis with insights for mitochondrial transplantation.
The physiological roles and pathological implications of metabolic communication via tunneling nanotubes in immune cells.
Peri-Ovarian Mitochondrial Administration Improves Surrogate Markers of Ovarian Function in Aged Rats: Free Versus Alginate-Encapsulated Mesenchymal Stromal Cell-Derived Mitochondria.
Mitochondrial transfer in cancer-immune crosstalk.
Platelet-derived mitochondrial transplantation expands respiratory reserve and extracellular matrix anabolism in primary osteoarthritic chondrocytes.
Coacervate protocells-mediated mitochondrial transplantation restores gut epithelial energetic homeostasis in ulcerative colitis.

Sci Adv. 2026 Oct 30. 12(44): eaeg5364

Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.

John Soukar, Kayli Jones, Natalie M Garza, Valeria Duran Salas, Shounak Roy, Vishal M Gohil, Akhilesh K Gaharwar.

Cells exhibit innate reparative communication, enabling the exchange of bioactive molecules and, in some cases, entire organelles. Harnessing this endogenous process of intercellular organelle transfer represents an emerging therapeutic paradigm for restoring cellular function in diseases driven by organelle dysfunction. Mitochondrial transfer has gained prominence for its ability to restore bioenergetic capacity, mitigate oxidative stress, and rescue metabolic function in cells with impaired mitochondrial activity. Given that genetic or acquired defects in mitochondrial function are associated with diverse pathologies, including neurodegeneration, cardiovascular diseases, metabolic disorders, skeletal muscle defects, immune dysregulation, and age-associated decline, mitochondrial transfer offers broad therapeutic potential. Mitochondrial transfer seeks to deliver functional mitochondria to injured cells to reestablish metabolic competence. However, insufficient organelle trafficking and limited control over transfer dynamics remain critical barriers to clinical translation. Recent biotechnological developments aimed at enhancing donor-recipient connectivity, increasing mitochondrial availability, and modulating transfer machinery have begun to address some of these key challenges. This review highlights recent advances in mitochondrial transfer bioengineering, emerging therapeutic applications, and key challenges that must be resolved to enable clinical deployment.

DOI: https://doi.org/10.1126/sciadv.aeg5364
Adv Sci (Weinh). 2026 Oct 25. pii: e78392. [Epub ahead of print]

Donor-Cell Senescence Redirects PINK1-Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3-Stabilized HSPA9.

Zixuan Ou, Mingke Zhao, Zhiwei Ling, Lianqi Peng, Bide Tong, Huaizhen Liang, Hongchuan Wang, Di Wu, Yifan Du, Zhi Du, Shihao Zhang, Yuyuan Jia, Yifan Qian, Gan Xu, Liuliang He, Gang Li, Shun Zhang, Lei Tan, Kun Wang, Xiaobo Feng, Cao Yang, Zhiwei Liao.

  Extracellular vesicle therapies have been developed for tissue repair, but how donor-cell senescence reshapes vesicle-mediated mitochondrial transfer remains unclear. Here, we show that senescent adipose-derived stem cells (ADSCs) redirect damaged mitochondria into microvesicles (MVs), converting protective vesicles into pro-degenerative carriers. Senescent ADSC-derived MVs are enriched in PINK1-marked, oxidatively damaged mitochondrial cargo. After transfer to nucleus pulposus cells (NPCs), this cargo disrupts recipient mitochondrial homeostasis, activates the cGAS-STING-NLRP3 inflammatory axis, and aggravates intervertebral disc degeneration. Proteomic and functional analyses identify HSPA9 as a mitochondrial cargo-sorting adaptor. Senescent stress induces SUMO3 conjugation of HSPA9 at K612, stabilizing HSPA9 by limiting ubiquitin-proteasomal degradation. Stabilized HSPA9 uses its peptide-binding domain to engage the kinase domain of activated PINK1 and links PINK1-positive damaged mitochondria to Annexin A1-associated MV structures. This SUMO3-HSPA9-PINK1 module diverts damaged mitochondria from PINK1-Parkin mitophagy toward MV-mediated mitochondrial transfer. Donor-cell reprogramming that restrains the release of damaged mitochondria and reinforces mitophagic clearance restores the in vivo therapeutic efficacy of senescent ADSC-derived MVs. These findings identify mitochondrial cargo fate as a switch between vesicle-mediated repair and degeneration.

Keywords:  SUMOylation; cellular senescence; intervertebral disc degeneration; microvesicles; mitochondrial transfer

DOI:  https://doi.org/10.1002/advs.78392
Mol Neurobiol. 2026 Oct 30. pii: 1003. [Epub ahead of print]63(1):

Intercellular Mitochondria Transfer as a Bioenergetic Rescue Mechanism in CNS Injury: Mechanisms, Therapeutic Potential, and Translational Barriers.

Afra Wasama Islam, Swapna Bejoy, Prarthana Motdhare, Afrah Riyas, Chris Puthenpurayil Abraham, Mehadiya Afreen Hussain.

  Acute central nervous system (CNS) injuries, including ischemic stroke, traumatic brain injury, and spinal cord injury, are characterized by profound mitochondrial dysfunction that drives secondary neuronal damage through ATP depletion, oxidative stress, and calcium dysregulation. Neuronal survival is critically dependent on mitochondrial integrity, making bioenergetic failure a central determinant of injury progression. In this context, intercellular mitochondria transfer has emerged as a potential adaptive mechanism through which functional mitochondria are delivered from donor cells-primarily astrocytes, microglia, and mesenchymal stem cells-to metabolically compromised neurons. Mitochondria transfer occurs via both contact-dependent pathways, such as tunneling nanotubes, and contact-independent mechanisms, including extracellular vesicles and free mitochondrial release. These processes are regulated by signaling pathways such as CD38/cADPR-mediated calcium flux and MIRO1-dependent mitochondrial trafficking, facilitating organelle mobilization and uptake. Functionally, transferred mitochondria have been associated with improved oxidative phosphorylation, reduced reactive oxygen species accumulation, altered calcium homeostasis, and modulation of survival pathways including PI3K/Akt and MAPK/ERK signaling in selected experimental models; however, the extent to which these effects are directly dependent on mitochondria transfer remains incompletely established. Preclinical evidence across multiple CNS injury models demonstrates improved neuronal viability, enhanced synaptic function, and attenuation of neurodegenerative processes following mitochondria transfer. However, whether mitochondria transfer represents a primary driver of neurorepair or a secondary compensatory response remains unresolved. In addition, inconsistencies in mechanistic pathways, variability in transfer efficiency, and limited reproducibility across experimental systems hinder translational interpretation. Therapeutic approaches including exogenous mitochondria transplantation, stem cell-mediated delivery, and bioengineered mitochondrial systems show promise but face substantial barriers related to targeting specificity, mitochondrial viability, immunogenicity, and lack of standardized protocols. This review critically evaluates the molecular mechanisms, functional consequences, and therapeutic potential of intercellular mitochondria transfer in CNS injury. It further highlights key limitations and knowledge gaps that must be addressed to determine whether mitochondria transfer can be effectively harnessed as a clinically viable strategy for neuro-restoration.

Keywords:  Central nervous system injury; Intercellular mitochondria transfer; Mitochondrial dysfunction; Neuronal bioenergetics; Neuroprotection

DOI:  https://doi.org/10.1007/s12035-026-06303-y
Signal Transduct Target Ther. 2026 Oct 26. pii: 469. [Epub ahead of print]11(1):

Encapsulated mitochondrial transplantation: Advancing organelle therapeutics.

Hae-Jun Yang, Pil-Soo Jeong, Sun-Uk Kim.

DOI: https://doi.org/10.1038/s41392-026-02959-z
Bioact Mater. 2027 Mar;69 651-666

Mitochondria-rich cytochalasomes as an intravenously deliverable vesicle platform for ischemic heart disease.

Xiong Gao, Lu Zhang, Lei Xu, Yawei Jin, Benheng Qian, Yuning Zhang, Mohan Li, Ze Yuan, Yihua Lu, Nan Qiu, Peng Wang, Xiaolei Sun, Junbo Ge, Aijun Sun.

  Poor organelle viability and rapid immune clearance limit mitochondrial transplantation for ischemic disease. Here, we engineer mitochondria-rich cytochalasomes (MRCs) as an intravenously deliverable vesicle platform. MRCs are generated through cytoskeletal remodeling in mesenchymal stem cells. They encapsulate functional mitochondria, protecting them from extracellular stressors and inheriting immunomodulatory proteins, which reduce macrophage phagocytosis by more than sixfold. Mechanistically, MRCs do not fuse with the host mitochondrial network but instead are trafficked to lysosomes and trigger protective autophagy-lysosomal response. In a murine myocardial ischemia/reperfusion (I/R) model, a single intravenous injection of MRCs reduced infarct size by 52% and preserved cardiac function for up to 28 days, whereas isolated mitochondria were ineffective. This work positions MRCs as a promising intravenously deliverable vesicle platform for ischemic heart disease and reveals a non-fusogenic mechanism.

Keywords:  Autophagy; Endothelial protection; Extracellular vesicles; Mitochondria-rich cytochalasomes; Mitochondrial transplantation; Myocardial ischemia/reperfusion injury

DOI:  https://doi.org/10.1016/j.bioactmat.2026.09.036
Medicina (Kaunas). 2026 Oct 09. pii: 1951. [Epub ahead of print]62(10):

Effects of Stem Cell-Derived Mitochondrial Transfer on H2O2-Induced Oxidative Stress in COV434 Granulosa Cells.

Selenay Furat, Candan Altuntaş, Kamil Can Kiliç.

  Background and Objectives: Oxidative stress-induced mitochondrial dysfunction contributes to granulosa cell apoptosis and ovarian dysfunction. This study investigated the therapeutic potential of human Wharton's jelly-derived mesenchymal stem cell-derived mitochondria (hWJ-MSCs-mito) in an H2O2-induced oxidative stress model of COV434 granulosa cells. Materials and Methods: Oxidative stress was induced using increasing concentrations of H2O2, and cell viability was assessed by the WST-8 assay. Isolated hWJ-MSC-mito were labeled with TMRM, transferred into COV434 cells, and confirmed by confocal microscopy. The expression of oxidative stress- and mitochondrial-related genes (CYP19A1, GPX1, HO1, SOD1, and TOMM20) was analyzed by qRT-PCR, whereas proliferative and apoptotic responses were evaluated by PCNA and active caspase-3 immunofluorescence, respectively. Results: Exposure to 1.5 mM H2O2 reduced cell viability by approximately 50%, establishing an oxidative stress model, while 10 µg hWJ-MSCs-mito provided an optimal mitochondrial dose. Transferred mitochondria were successfully internalized by recipient cells and enhanced cell viability, increased PCNA immunoreactivity, and reduced active caspase-3 immunoreactivity. Furthermore, it attenuated H2O2-induced upregulation of CYP19A1 and HO1, moderately reduced SOD1 expression, preserved GPX1 expression, and showed a modest increase in TOMM20 expression. Conclusions: hWJ-MSC-mito supplementation was associated with improved cell viability, increased PCNA immunoreactivity, reduced active caspase-3 immunoreactivity, and modulation of selected transcriptional responses in H2O2-treated COV434 cells. These findings support further investigation of mitochondrial supplementation in oxidative stress-induced granulosa cell injury.

Keywords:  apoptosis; granulosa cells; mesenchymal stem cells; mitochondrial transfer; oxidative stress

DOI:  https://doi.org/10.3390/medicina62101951
Sci Adv. 2026 Oct 30. 12(44): eaef8069

Photosynthetic chimeric stem cells function as mitochondrial batteries.

Zhengtai Chen, Hanxiao Sun, Yuanyang Zheng, Xuan Jiang, Yan He, Kai Ye, Yufan Zhang, Zhengwei Mao, Ziyi Zhou, Xiaoxi Lin, Chenggang Yi, Wei Wang.

Therapies built on mitochondrial transfer hold promise for repairing dysfunctional, energy-deficient cells. Still, mesenchymal stem cells used as mitochondrial donors are limited by poor engraftment, risk of aberrant differentiation, and low transfer efficiency. Herein, we constructed photosynthesis-empowered cross-kingdom chimeric stem cells (PCSs; "mitochondrial battery") by introducing plant-derived thylakoid-based artificial nuclei plus FGF21-encoding messenger RNA (mRNA) into enucleated bone marrow mesenchymal stem cells. Photosynthetic activity enhances mitochondrial transfer to restore metabolism in damaged cells and elevates anabolism to increase FGF21 production. Sustained FGF21 release promotes mitochondrial biogenesis and sustains long-term cellular energy homeostasis. Mouse and porcine wound healing models demonstrate that PCSs recharge cellular energy to accelerate wound repair. This light-activated cellular photosynthetic platform supports modular mRNA programmability, shows no engraftment or aberrant differentiation, and allows repeated administration for diverse therapeutic applications.

DOI: https://doi.org/10.1126/sciadv.aef8069
Pharmacol Res. 2026 Oct 27. pii: S1043-6618(26)01623-3. [Epub ahead of print]234 109708

Mitochondrial transplantation as a therapeutic strategy: From energy replacement to metabolic and immune reprogramming.

Chuli Zhu, Meng Xu, Yanan Ji, Jie Wang, Xinlei Yao, Hualin Sun.

  Mitochondrial dysfunction drives diseases, including ischemia-reperfusion injury, neurodegenerative disorders, cardiovascular disease, metabolic syndrome, and inflammation. Conventional mitochondria-targeted strategies offer only partial rescue and are insufficient for severe, irreversible damage. Mitochondrial transplantation (MT)-the delivery of exogenously isolated functional mitochondria to injured cells-has emerged as a promising therapeutic strategy that directly restores mitochondrial bioenergetic function and may subsequently modify the tissue microenvironment. This Review examines the entire MT pipeline, from mitochondrial source selection, isolation and preservation, to in vivo delivery strategies. We critically examine the multiple mechanisms underlying MT's therapeutic efficacy, including cellular uptake and intracellular integration, energy restoration and metabolic reprogramming, redox rebalancing, remodeling of mitochondrial quality control (fusion/fission, mitophagy, biogenesis), and immunomodulation. We summarize preclinical and clinical applications across multiple organ systems-heart, nervous system, liver, kidney, lung, skeletal muscle, retina-as well as in oncology and aging. We analyze five major translational bottlenecks: the lack of standardized manufacturing protocols, undefined dose-response relationships, immunogenicity and long-term safety uncertainties, the decisive impact of mitochondrial heterogeneity, and regulatory ambiguity. We outline future directions-mechanistic deepening, engineered target delivery, individualized mitochondrial medicine, combinatorial regimens, and a phased clinical roadmap. MT is not merely energy supplementation; it may reshape cellular metabolism, quality control networks, and immune microenvironments, representing a shift from pharmacological modulation of mitochondrial function toward organelle replacement strategies. Despite challenges, these advances may facilitate individualized mitochondrial therapies as a proposed future direction.

Keywords:  Clinical translation; Individualized mitochondrial medicine; Metabolic reprogramming; Mitochondrial dysfunction; Mitochondrial quality control; Mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.phrs.2026.109708
Exp Gerontol. 2026 Oct 29. pii: S0531-5565(26)00352-9. [Epub ahead of print] 113372

Mitochondrial acquisition after the Asgard revolution: Reconstructing eukaryogenesis with insights for mitochondrial transplantation.

Yuan-Yuan Li, Kevin B Frazier, Franklin R Tay.

  Mitochondria arose from an alphaproteobacterial endosymbiont that became integrated within an archaeal host during eukaryogenesis. The discovery of Asgard archaea has clarified host ancestry and supports reconstructions in which aspects of cytoskeletal and membrane complexity preceded mitochondrial acquisition. Organellogenesis involved genome reduction, gene transfer, protein import, metabolic coupling, and vertical inheritance. These evolutionary principles complement current mitochondrial transplantation recommendations by generating testable predictions about recipient dependence and the duration of rescue. Transplanted mitochondria are mature organelles introduced into cells already equipped to maintain mitochondria; the requirement for transient or durable function must nevertheless be tested for each indication. Aging can modify organelle delivery, recipient quality control, and tissue responses, with particular implications for the neurovascular unit and neuronal function. Extracellular vesicle delivery requires verification of mitochondrial cargo, potency, and compatibility. Measurable criteria distinguish delivery, uptake, cytosolic access, network interaction, persistence, and functional benefit, while separating evidence from aging, acute ischemia, and inherited disease models.

Keywords:  Asgard archaea; Endosymbiosis; Eukaryogenesis; Horizontal mitochondrial transfer; Mitochondrial transplantation; Organellogenesis

DOI:  https://doi.org/10.1016/j.exger.2026.113372
FEBS J. 2026 Oct 27.

The physiological roles and pathological implications of metabolic communication via tunneling nanotubes in immune cells.

Bingnan Chen, Di Wang, Ruohan Hu, Xiaobo Zhou, Hua Zhang.

  The traditional paradigm of intercellular communication is rapidly evolving. Tunneling nanotubes (TNTs) represent a distinct mode of intercellular communication, enabling the transfer of organelles, signaling molecules, and metabolic resources between spatially separated cells. Unlike soluble factor-mediated communication, TNTs establish direct physical connections that can support rapid and directional cargo transport, including mitochondrial transfer, with consequences for recipient-cell metabolism and function. In the immune system, TNT-mediated mitochondrial and other cargo transfer has been implicated in macrophage functional polarization, T-cell metabolic fitness, and natural killer (NK) cell-mediated immunity. In this review, we summarize the molecular characteristics of TNTs in immune cells, the regulation of their formation under inflammatory and metabolic stress, and the mechanisms and consequences of cargo transfer. We further examine the context-dependent nature of TNT-mediated communication, including its potential roles in host defense, tissue repair, tumor immune evasion, and pathogen dissemination. Finally, we critically evaluate transfer kinetics, quantitative scale, prevalence, in vivo evidence, and the technical limitations that currently constrain causal attribution and therapeutic translation.

Keywords:  immune cells; metabolic communication; mitochondrial transfer; tunneling nanotubes

DOI:  https://doi.org/10.1111/febs.70783
Biomedicines. 2026 Oct 20. pii: 2394. [Epub ahead of print]14(10):

Peri-Ovarian Mitochondrial Administration Improves Surrogate Markers of Ovarian Function in Aged Rats: Free Versus Alginate-Encapsulated Mesenchymal Stromal Cell-Derived Mitochondria.

Zehra Seda Halbutoğulları, Zeynep Ece Utkan Korun, Gülşen Çelebi, Selenay Furat, Meryem Dişli, Gökhan Duruksu, Tijen Utkan.

  Background: Ovarian aging is driven in part by mitochondrial dysfunction, and transfer of exogenous mitochondria has been proposed as a cell-free alternative to stem cell therapy; whether the delivery format alters efficacy has not been tested directly. Methods: We compared free and alginate-encapsulated mitochondria isolated from rat bone marrow-derived mesenchymal stromal cells (BM-MSCs) in aged rats. Mitochondria retained their membrane potential after encapsulation; approximately 35% of the encapsulated protein was released within 1 h in vitro, and release was complete by 24 h. Thirty-five female Wistar rats were allocated to five groups (n = 7): young control (Y-Ctrl), aged control (O-Ctrl), and three aged subgroups receiving empty capsules (Alg), free mitochondria (MSC-Mito), or encapsulated mitochondria (MSC-Mito@Alg), administered peri-ovarianly and evaluated on day 14. Results: Both treatments were associated with higher primordial and secondary follicle numbers, fewer atretic follicles, higher estradiol, higher Esr1, Fshr, and Sod2 expression, lower Casp3 and Mct4 expression, and lower Caspase-3 and higher Ki-67 immunoreactivity relative to aged controls. Anti-Müllerian hormone, Nrf2, and Tomm20 were higher only with MSC-Mito@Alg; corpus luteum counts were higher only with MSC-Mito. Although empty capsules were not inert, peri-ovarian mitochondrial administration improved follicular, endocrine, and molecular indices of ovarian aging. Conclusions: The encapsulated formulation was associated with additional effects on antioxidant and mitochondrial-mass endpoints but was not uniformly superior to free mitochondria.

Keywords:  alginate; folliculogenesis; mesenchymal stromal cells; mitochondrial transfer; ovarian aging; ovarian reserve

DOI:  https://doi.org/10.3390/biomedicines14102394
Biochim Biophys Acta Mol Basis Dis. 2026 Oct 27. pii: S0925-4439(26)00382-0. [Epub ahead of print]1873(2): 168516

Mitochondrial transfer in cancer-immune crosstalk.

Yuhan Chen, Zhangui Tang, Jingyi Cheng.

  Mitochondrial transfer has emerged as a pivotal mechanism of intercellular metabolic reprogramming within the tumor microenvironment (TME), fundamentally reshaping cancer-immune crosstalk. This review provides a comprehensive synthesis of the regulatory triggers, molecular routes, and functional consequences of mitochondrial transfer in the tumor immune microenvironment. Mitochondrial exchange between tumor and immune cells occurs bidirectionally via tunneling nanotubes, extracellular vesicles, and other pathways, and is dynamically regulated by reactive oxygen species, inflammatory signaling, and metabolic stress. We delineate how this transfer exerts dual effects on antitumor immunity: tumor cells hijack functional mitochondria from T cells, macrophages, and stromal cells to fuel their proliferation and therapy resistance, while simultaneously delivering mutant mitochondria to immune cells to drive exhaustion and immune evasion. Conversely, artificial mitochondrial transfer to immune cells-including repolarization of tumor-associated macrophages via M1-derived mitochondria and metabolic augmentation of T cells and natural killer cells-demonstrates significant potential to reinvigorate antitumor immunity and overcome resistance to immune checkpoint blockade. We further discuss emerging strategies to block pro-tumoral mitochondrial hijacking through cytoskeletal inhibitors and extracellular vesicle modulators. Critical challenges for clinical translation-including precision delivery, sustained functional integration, mitochondrial DNA heteroplasmy risks, and interactions with conventional therapies-are also addressed. By integrating mechanistic insights with therapeutic innovation, this review positions mitochondrial transfer as both a targetable driver of immunosuppression and a platform for next-generation cancer immunotherapies.

Keywords:  Artificial mitochondrial transfer; Immune evasion; Mitochondrial transfer; Tumor microenvironment; cancer immunotherapy

DOI:  https://doi.org/10.1016/j.bbadis.2026.168516
J Transl Med. 2026 Aug 20. pii: 1363. [Epub ahead of print]24(1):

Platelet-derived mitochondrial transplantation expands respiratory reserve and extracellular matrix anabolism in primary osteoarthritic chondrocytes.

Nicole Jeraldo-Araya, Liliana Yantén-Fuentes, María Paz Hernández-Cáceres, Jonathan Morales-Reyes, Ana María Vega-Letter, Eliana Lara-Barba, Cesar Merino-Flores, Felipe A Bustamante-Barrientos, Iván Alfaro, Andrea Matamoros, Álvaro A Elorza, Camila García-Navarrete, Noymar Luque-Campos, Maximiliano Barahona, Claudia Altamirano, Patricia Luz-Crawford, Pablo Cruz, Jorge A Toledo.

   BACKGROUND: Osteoarthritis (OA) is a leading cause of disability worldwide, driven by the complex interplay of aging, obesity, and mechanical stress, which converge on progressive deterioration of cartilage, subchondral bone, and synovial tissue. Current treatments alleviate symptoms but fail to halt the degenerative process, making joint replacement surgery the only definitive option for advanced disease. A central mechanism underlying OA pathogenesis is mitochondrial dysfunction in chondrocytes, in which the balance between oxidative phosphorylation (OXPHOS) and glycolysis is disrupted, leading to impaired OXPHOS, accumulation of reactive oxygen species (ROS), and sustained overproduction of matrix-degrading enzymes and pro-inflammatory cytokines. Mitochondrial transplantation has emerged as a promising strategy to restore cellular bioenergetics, and platelets, which contain functional, respiration-competent mitochondria, represent an accessible allogenic donor source.
METHODS: Mitochondria isolated from platelets of healthy donors were structurally and functionally characterized and transplanted into primary human OA chondrocytes by mitoception at increasing chondrocyte-to-mitochondria ratios. Internalization was assessed by flow cytometry and confocal colocalization analysis. Bioenergetic effects were quantified by Seahorse extracellular flux analysis; mitochondrial membrane potential and superoxide production were measured by flow cytometry; extracellular matrix protein expression was evaluated by immunofluorescence and RT-qPCR; and the inflammatory secretome was profiled by Luminex multiplex assay.
RESULTS: Isolated platelet mitochondria preserved outer membrane integrity, membrane potential, and ADP-coupled respiratory activity prior to transplantation. They were efficiently internalized by OA chondrocytes in a dose-dependent manner, with optimal uptake observed at chondrocyte-to-platelet-equivalent mitochondria dose ratios of 1:100. Transplantation increased maximal respiratory capacity and spare respiratory reserve without altering basal respiration, was accompanied by elevated type II collagen and aggrecan protein levels, and selectively reduced secreted IL-1β and osteopontin while leaving IL-6, TNF-α, IL-10, and IL-1RA unchanged. Mitochondrial superoxide production was modestly increased and was prevented by the mitochondria-targeted antioxidant MitoTEMPO, while mitochondrial membrane potential remained unchanged.
CONCLUSIONS: Platelet-derived mitochondrial transplantation expands the respiratory reserve and modulates the catabolic-anabolic balance of human OA chondrocytes without inducing mitochondrial depolarization, providing a mechanistic basis for allogenic, blood-derived mitochondrial therapies in joint disease.

Keywords:  Chondrocyte bioenergetics; Extracellular matrix remodeling; Mitochondrial transplantation; Osteoarthritis; Platelet-derived mitochondria

DOI:  https://doi.org/10.1186/s12967-026-08809-4
Bioact Mater. 2027 Mar;69 682-702

Coacervate protocells-mediated mitochondrial transplantation restores gut epithelial energetic homeostasis in ulcerative colitis.

Bingyu Ding, Yumo Chen, Yiying Jia, Jiarui Li, Zhouyang Tan, Weilan Wu, Shenyuan Ouyang, Bingjie Tong, Lifen Wang, Helin Xu.

  Ulcerative colitis (UC) is closely linked to mitochondrial dysfunction in intestinal epithelial cells, yet current therapies fail to correct underlying energy metabolism defects. While exogenous mitochondrial transplantation offers a promising strategy, its clinical translation is hindered by rapid loss of mitochondrial bioactivity ex vivo, poor delivery efficiency, and lysosomal degradation following cellular uptake. Here, we developed a biomimetic coacervate-based protocell system (HTP) via liquid-liquid phase separation of polyethylene glycol, tannic acid, and sodium hyaluronate for efficient encapsulation and delivery of functional mitochondria (HTP@Mito). HTP protocells preserved mitochondrial membrane potential and ATP synthesis capacity for up to 72 h in HBSS buffer at 37°C, far exceeding the viability of free mitochondria. Notably, HTP markedly enhanced intracellular delivery of isolated mitochondria via lipid-raft-mediated endocytosis. In a dextran sulfate sodium (DSS)-induced murine UC model, rectally administrating HTP@Mito achieved superior therapeutic efficacy via restoring ATP levels and mitochondrial membrane potential, scavenging reactive oxygen species (ROS). Furthermore, by reducing oxidative stress, HTP@Mito rescued lysosomal function and restored impaired autophagic flux, thereby promoting mitophagy to clear damaged mitochondria. HTP@Mito treatment also repaired intestinal epithelial tight junctions, restored goblet cell-derived mucus secretion, and rebalanced gut microbiota by increasing beneficial Lachnospiraceae while reducing pathogenic Escherichia-Shigella. Collectively, this work established a versatile, biomimetic organelle delivery platform that could correct mitochondrial energy deficiency in the intestinal epithelium, providing a framework for mitochondrial transplantation in ulcerative colitis.

Keywords:  Coacervates; Mitochondrial transplantation; Mitophagy; Protocells; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.bioactmat.2026.10.023