bims-mitrat 2026-04-19 papers

Front Immunol. 2026 ;17 1743261

Mitochondrial transfer as a driver of immune microenvironment remodeling.

Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi, Zuojiong Gong.

Mitochondria are central regulators of immunometabolism, and emerging evidence identifies intercellular mitochondrial transfer as a key driver of immune microenvironment remodeling. Beyond energy production, transferred mitochondria reshape immune niches by reprogramming metabolic fitness, redox balance, inflammatory tone, and immune cell interactions. Through multiple transfer routes, including tunneling nanotubes, extracellular vesicles, and gap junctions, mitochondrial exchange modulates immune activation, immunosuppression, and tolerance across diverse physiological and pathological contexts. In this review, we summarize current mechanisms of mitochondrial transfer and highlight how this process directionally remodels the immune microenvironment in inflammation, cancer, and autoimmune diseases. We further discuss therapeutic strategies aimed at modulating mitochondrial transfer to reprogram immune responses, providing new perspectives for immunomodulation and disease intervention.

Keywords: cancer; immune cell; immune microenvironment; inflammation; mitochondria transfer

DOI: https://doi.org/10.3389/fimmu.2026.1743261

bioRxiv. 2026 Apr 07. pii: 2026.04.06.716722. [Epub ahead of print]

Mitochondrial Transplantation in the Eye: A Review and Evaluation of Surgical Approaches.

Bertan Cakir, Tsai-Chu Yeh, Cheng-Hui Lin, Man-Ru Wu, Éric Boilard, Martin Pelletier, Aneal M Singh, Yann Breton, Samir Patel, Tom Benson, David Rp Almeida, Sui Wang, Vinit B Mahajan.

Purpose: Mitochondrial dysfunction contributes to major blinding diseases, including age-related macular degeneration and glaucoma. Although mitochondrial transplantation has shown therapeutic potential in multiple organ systems, translation to the eye remains limited, partly due to uncertainty regarding optimal delivery. We summarize the biologic rationale and preclinical evidence supporting ocular mitochondrial transplantation and present feasibility data evaluating clinically relevant delivery routes.
Methods: We conducted a focused narrative review of ocular mitochondrial transplantation. For feasibility experiments, mitochondria with an endogenous fluorescent dye were isolated from liver donor mice. Postnatal day 7 pups received subretinal injections, and adult CD1 mice received intravitreal injections, including optic nerve head directed delivery. Eyes were analyzed using fluorescence microscopy and immunohistochemistry. Mitochondrial uptake was assessed in cultured retinal pigmental epithelial (RPE) cells using co-incubation assays. Suprachoroidal delivery feasibility was evaluated in cadaveric human near-real surgical specimens using a novel dedicated suprachoroidal injector.
Results: The literature on ocular mitochondrial transplantation remains limited and consists primarily of small preclinical studies using intravitreal delivery and imaging-based detection. In our experiments, intravitreal delivery produced donor signals predominantly within inner retinal layers, with enrichment along retinal nerve fiber bundles when directed toward the optic nerve head. Cultured RPE cells demonstrated dose-dependent uptake of exogenous mitochondria. Subretinal delivery localized donors signal to the RPE and adjacent outer retina. Suprachoroidal injections demonstrated procedural feasibility with reliable access to the suprachoroidal space and visible injectate distribution.
Conclusions: Ocular mitochondrial transplantation is in an early stage of investigation. Our feasibility data indicate that established posterior-segment delivery routes expose distinct retinal compartments and that route selection strongly influences anatomic distribution. Further studies are needed to verify intracellular uptake, define dosing and durability, and evaluate safety in disease-relevant models.

DOI: https://doi.org/10.64898/2026.04.06.716722

Nat Rev Nephrol. 2026 Apr 14.

Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.

James D McCully, Aybuke Celik, Amish Asthana, Giuseppe Orlando.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to global morbidity and mortality, with limited treatment options beyond supportive care. Mitochondrial dysfunction is a shared feature of both conditions, driving impaired energy production, oxidative stress and cell death. Owing to its reliance on oxidative phosphorylation, the kidney is especially vulnerable to ischaemia-reperfusion injury, a leading cause of AKI and a risk factor for long-term loss of kidney function. Persistent mitochondrial damage contributes to the transition from AKI to CKD, and strategies aimed at restoring mitochondrial health, therefore, have therapeutic potential. Here, we focus on mitochondrial transplantation, a therapeutic approach that delivers viable, respiratory-competent mitochondria to injured tissue to support recovery. Mitochondria for transplantation can be isolated from a variety of sources (autologous or allogeneic) without triggering an immune, autoimmune or inflammatory response, or a reaction to damage-associated molecular patterns. Isolated mitochondria can be delivered by intra-arterial injection, and, once in the target organ, they are rapidly integrated into the cells through endocytosis. Mitochondrial transplantation supports the restoration of mitochondrial function and associated signalling pathways, promoting enhanced organ function and cellular viability. Several preclinical studies have demonstrated improved kidney function, reduced inflammation and preserved mitochondrial structure following mitochondrial therapy in models of ischaemia.

DOI: https://doi.org/10.1038/s41581-026-01072-2

Nature. 2026 Apr 15.

Cell-type-targeted mitochondrial transplantation rescues cell degeneration.

A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy1-3. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here we developed MitoCatch as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells by cell-surface-displayed monospecific binders, mitochondrion-displayed monospecific binders or bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondrial delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons and cardiac, endothelial and immune cells in humans and mice. Transplanted mitochondria promoted the survival of damaged neurons from an individual with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a potential strategy to target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41586-026-10391-0

Stem Cells. 2026 Apr 09. pii: sxag019. [Epub ahead of print]

Stem cells enhance mitochondrial function in experimental Huntington's disease.

Francesco D'Egidio, Napasiri Putthanbut, Michaela Starahs, Jea Young Lee, Cesario V Borlongan.

Huntington's Disease (HD) is a neurodegenerative disorder caused by CAG triplet expansion in the HTT gene, producing a mutant Huntingtin protein that impairs mitochondrial dynamics by reducing fusion and increasing fission. Mesenchymal stem cells (MSCs) have shown potential therapeutic effects by sharing functional mitochondria and other secretomes. In this study, quinolinic acid-lesioned neuro-2a (QA-N2a) cells and glutamatergic neurons with 50 CAG repeats (HD neurons) were co-cultured with human umbilical cord-derived MSCs for 5 hours. For QA-N2a cells, immunocytochemistry was performed to demonstrate change in GABA and Substance P before and after co-culture. For HD neurons, immunocytochemistry was conducted to identify mitochondrial proteins, while Western Blot was employed to evaluate proteins related to inflammation and mitochondrial function. As a result, co-culture with MSC significantly restored the expression of GABA and Substance P, which diminished after QA exposure. In HD neurons co-cultured with MSCs, an increase in mitochondrial abundance was observed, with significantly higher intensity and dendritic distribution of mitochondria compared to control cells. Western Blot analysis confirmed this increase and showed a rising trend in ATP5a levels. MSCs also promoted mitochondrial fusion, indicated by higher levels of Mitofusin 2 (MFN2) and Mitochondrial Dynamin Like GTPase (OPA1), and a trend of reduction in the fission marker Dynamin-Related Protein (DRP1). Additionally, the co-culture led to a decreased trend in neuroinflammation markers IL-6, TNF-α, MMP9, and p-NFkB. Collectively, this study demonstrates that MSCs alleviate HD pathology by restoring mitochondria activity and potentially suppressing inflammation in two different HD in vitro models.

Keywords: Huntington’s disease; cell-free therapy; mesenchymal stem cells; mitochondrial transfer; secretome

DOI: https://doi.org/10.1093/stmcls/sxag019

Front Pharmacol. 2026 ;17 1774791

Platelet mitochondria dysfunction in diabetes mellitus: mechanisms and therapeutic implications.

Srikanth Yadava, Harikrishna Reddy Dontiboina, Sajusha Dugluri, Ganesh Yadagiri, Priyanka Choudhury, Ramakrishna Kakarla.

Platelets play a pivotal role in hemostasis, thrombosis, and inflammation, and their dysfunction in diabetes significantly contributes to vascular complications such as ischemic stroke, myocardial infarction, and peripheral artery disease. This review explores the mechanisms underlying platelet hyperactivity in diabetes, emphasizing the critical involvement of platelet mitochondria. Hyperglycemia, insulin resistance, oxidative stress, advanced glycation end products, calcium dysregulation, and protein kinase C activation all converge to impair platelet mitochondrial function, leading to increased reactive oxygen species, altered bioenergetics, and defective mitophagy. These changes promote a pro-thrombotic and pro-inflammatory state, exacerbating vascular injury. Furthermore, the review highlights emerging therapeutic strategies targeting platelet mitochondria, including pharmacological agents, mitochondrial antioxidants, and even mitochondrial transplantation, to restore platelet function and mitigate vascular risks in diabetic patients. Understanding the intricate relationship between platelet mitochondria and diabetes opens new avenues for preventing and treating diabetic vascular complications.

Keywords: diabetes; platelet aggregation; platelet energy; platelet mitochondria; platelets; thrombosis; vascular complications

DOI: https://doi.org/10.3389/fphar.2026.1774791