bims-mitrat 2025-02-16 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–02–16
six papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.
Mitochondrial transplantation improves outcomes after cardiac arrest and resuscitation in mice.
In Vivo and In Vitro Evaluation of the Feasibility and Safety Profiles of Intraarticular Transplantation of Mitochondria for Future Use as a Therapy for Osteoarthritis.
Transfer of Mitochondria from Healthy Stem Cells to Injured Cells in Stroke with Retinal Impairments.
Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss.
Peripheral mitochondrial transplantation alleviates diabetes-associated cognitive dysfunction by suppressing cuproptosis.

FEBS J. 2025 Feb 11.

Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.

Julie Sofie Bjerring, Yara Khodour, Emilee Anne Peterson, Patrick Christian Sachs, Robert David Bruno.

  The mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) by which this alteration occurs has yet to be defined. Here, we test the hypothesis that mitochondrial transfer from normal mammary epithelial cells to breast cancer cells plays a role in this redirection process. We evaluate mitochondrial transfer in 2D and 3D organoids using our unique 3D bioprinting system to produce chimeric organoids containing normal and cancer cells. We demonstrate that breast cancer tumoroid growth is hindered following interaction with mammary epithelial cells in both 2D and 3D environments. Furthermore, we show mitochondrial transfer occurs between donor mammary epithelial cells and recipient cancer cells primarily through tunneling nanotubes (TNTs) with minimal amounts seen from extracellular transfer of mitochondria, likely via extracellular vesicles (EVs). This organelle exchange results in various cellular and metabolic alterations within cancer cells, reducing their proliferative potential, and making them susceptible to microenvironmental control. Our results demonstrate that mitochondrial transfer contributes to microenvironmental redirection of cancer cells through alteration of metabolic and molecular functions of the recipient cancer cells. To the best of our knowledge, this is the first description of a 3D bioprinter-assisted organoid system for studying mitochondrial transfer. These studies are also the first mechanistic insights into the process of mammary microenvironmental redirection of cancer and provide a framework for new therapeutic strategies to control cancer.

Keywords:  3D bioprinting; breast cancer; cellular redirection; microenvironment; mitochondrial transfer

DOI:  https://doi.org/10.1111/febs.70002
Resuscitation. 2025 Feb 11. pii: S0300-9572(25)00047-4. [Epub ahead of print] 110535

Mitochondrial transplantation improves outcomes after cardiac arrest and resuscitation in mice.

Tomoaki Aoki, Yusuke Endo, Tai Yin, Jacob S Kazmi, Cyrus E Kuschner, Jun Hagiwara, Kanako Ito-Hagiwara, Eriko Nakamura, Lance B Becker, Kei Hayashida.

   INTRODUCTION: Mitochondrial transplantation (MTx) is an emerging strategy for restoring cellular bioenergetics and mitigating ischemia-reperfusion (IR) injury. We previously demonstrated that MTx improved neurological outcomes and survival in a rat model of cardiac arrest (CA). However, the mechanisms underlying these benefits, particularly regarding immune modulation and transcriptional regulation, remain unclear.
METHODS: Adult C57BL/6 mice and Sprague-Dawley rats underwent CA and resuscitation protocols, followed by intravenous MTx with species-matched donor mitochondria. Survival and neurological outcomes were assessed up to 72 hours. Biodistribution and cellular uptake of fluorescent dye-labeled mitochondria were analyzed via in vivo imaging and flow cytometry. Gene expression related to mitochondrial dynamics, inflammation, and immune regulation was evaluated using qPCR.
RESULTS: MTx improved 72-hour survival (33.3% vs. 0%, P=0.006) and neurological scores compared to vehicle treatment. Reduced brain edema was observed in MTx-treated animals. Mitochondrial uptake was significantly enhanced in the brain and spleen post-CA, with key infiltrating and resident immune cell populations-including monocytes, macrophages, microglia, astrocytes, and endothelial cells-preferentially internalizing transplanted mitochondria. Circulating myeloid cells rapidly internalized functional mitochondria, with 53.9% uptake in MTx-treated CA animals versus 10.6% in controls (P<0.001). MTx also modulated immune profiles, reducing pro-inflammatory macrophages and enhancing cytotoxic T cell numbers. Gene expression analysis showed that MTx downregulated Fission 1, preserved Mitofusin 2, and upregulated protective genes, including Hmox1, Sirt1, and Entpd1.
CONCLUSIONS: MTx improves outcomes after CA, accompanied by mitochondrial uptake by immune cells and redistribution to injured tissues. This process likely modulates immune responses, enhances mitochondrial fusion, and activates cytoprotective gene expression.

Keywords:  Mitochondrial transplantation; cardiac arrest; immune response; ischemia reperfusion; survival

DOI:  https://doi.org/10.1016/j.resuscitation.2025.110535
Cells. 2025 Jan 21. pii: 151. [Epub ahead of print]14(3):

In Vivo and In Vitro Evaluation of the Feasibility and Safety Profiles of Intraarticular Transplantation of Mitochondria for Future Use as a Therapy for Osteoarthritis.

Carlos Vaamonde-Garcia, Tamara Hermida-Gómez, Sara Paniagua-Barro, Elena F Burguera, Francisco J Blanco, Mercedes Fernández-Moreno.

  Osteoarthritis (OA) is the most common rheumatologic disease and a major cause of pain and disability in older adults. No efficient treatment is currently available. Mitochondrial dysfunction in chondrocytes drives molecular dysregulation in OA pathogenesis. Recently, mitochondrial transfer to chondrocytes had been described, enabling transplant of mitochondria as a new avenue to modify the OA process, although evidence on its feasibility and safety remains limited.The primary objective of this study was to demonstrate the feasibility and safety of intra-articular mitochondrial transplantation. Mitochondria were isolated from liver using the procedure described by Preble and coworkers combined with magnetic beads coupled to anti-TOM22 antibodies. The organelles obtained were analyzed to determine their purity and viability. The safety and viability of the administration of the isolated mitochondria into articular tissues as well as the integration and distribution of the transplanted mitochondria within joint tissues were analyzed using both in vitro and in vivo models. We established an efficient, reproducible, effective, and rapid protocol for isolating mitochondria from liver. We obtained mitochondria with high viability, yield, and purity. The isolated mitochondria were injected into joint tissue using both in vitro and in vivo models. Functional mitochondria were detected in the extracellular matrix of the cartilage, menisci and synovium. Our results establish a safe and viable protocol for mitochondrial isolation and intra-articular injection. The methodology and findings presented here pave the way for future studies in osteoarthritis models to validate mitochondrial transplantation as a potentially effective treatment for OA.

Keywords:  cartilage; chondrocyte; in vitro model; in vivo model; mitochondria injection; mitochondria isolation; osteoarthritis; synovium

DOI:  https://doi.org/10.3390/cells14030151
Methods Mol Biol. 2025 Feb 11.

Transfer of Mitochondria from Healthy Stem Cells to Injured Cells in Stroke with Retinal Impairments.

Napasiri Putthanbut, Jea-Young Lee, Cesario V Borlongan.

  Stroke is the second leading cause of mortality worldwide, with retinal ischemia as its prominent complication. However, the pathology of retinal ischemia has not been fully elucidated, resulting in a lack of effective treatment. Stem cell therapy has been suggested to be therapeutic in retinal ischemia, with mitochondrial transfer potentially one of the underlying mechanisms. To investigate the mitochondrial function in retinal ischemia and the potential of mitochondrial transfer from mesenchymal stem cells (MSCs), in vivo middle cerebral artery occlusion (MCAO) model and in vitro oxygen-glucose deprivation (OGD) model were utilized in combination. In vivo, rats subjected to MCAO were randomly administered intravenous MSCs or vehicles. Laser doppler was used to measure the blood flow in the brain and the eye, along with immunohistochemical staining for assessing cellular degeneration. In vitro, retinal pigment epithelium (RPE) cells exposed to OGD were cocultured with or without MSCs. Mitochondrial function was measured by mitochondrial respiration, mitochondrial network analysis, mitochondria live cell imaging, and immunocytochemistry. The results demonstrated improved cell survival and restored mitochondrial function following MSC therapy. This chapter details the protocols necessary to produce the in vivo and in vitro models of ischemic stroke along with an assessment of mitochondrial function. Elucidating the mechanisms of mitochondrial transfer will further the knowledge in regenerative medicine and may enable new targets of therapeutics for stroke, especially for retinal ischemia.

Keywords:  Ischemic stroke; Middle cerebral artery occlusion; Mitochondria transfer; Mitochondrial function; Oxygen-glucose deprivation; Retinal ischemia; Stem cell therapy

DOI:  https://doi.org/10.1007/7651_2024_599
Acta Biomater. 2025 Feb 10. pii: S1742-7061(25)00106-0. [Epub ahead of print]

Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss.

Shi Cheng, Lu Zhou, Wu-Yin Wang, Meng-Jie Zhang, Qi-Chao Yang, Wen- Da Wang, Kong-Huai Wang, Zhi-Jun Sun, Lu Zhang.

  Inflammatory diseases frequently result in bone loss, a condition for which effective therapeutic interventions are lacking. Mitochondrial transfer and transplantation hold promise in tissue repair and disease treatments. However, the application of mitochondrial transfer in alleviating disorders has been limited due to its uncontrollable nature. Moreover, a key challenge in this field is maintaining the quality of isolated mitochondria (Mito), as dysfunctional Mito can exacerbate disease progression. Therefore, we employ Mito loading erythrocytes (named MiLE) to achieve maintenance of mitochondrial quality. In addition, MiLE can be cryopreserved, allowing for long-term preservation of mitochondrial quality and facilitating the future application of mitochondrial transfer. In the inflammatory microenvironment, MiLE supplying Mito as well as O2 to macrophages. By undergoing metabolic reprogramming, MiLE suppresses lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction. In summary, this work tackles the challenges of uncontrollable mitochondrial transfer and mitochondrial quality maintenance, and offers an opportunity for future exploration of organelle transplantation. STATEMENT OF SIGNIFICANCE: The application of mitochondrial transfer for the alleviation of pathologies has been hindered by the intrinsic limitations in terms of control and selectivity. Furthermore, maintaining mitochondrial integrity and functionality following isolation poses a significant challenge. In a pioneering approach, our research team developed a method for encapsulating mitochondria within erythrocytes, termed Mitochondria-Loading Erythrocytes (MiLE), which ensures extended mitochondrial functionality and controlled transfer. Within an inflammatory microenvironment, MiLE supplies both mitochondria and O2 to macrophages. By undergoing metabolic reprogramming, MiLE alleviates lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction.

Keywords:  Inflammatory bone loss; Mitochondria-loading erythrocytes; Mitochondrial transfer

DOI:  https://doi.org/10.1016/j.actbio.2025.02.024
Brain Res Bull. 2025 Feb 07. pii: S0361-9230(25)00057-7. [Epub ahead of print]222 111245

Peripheral mitochondrial transplantation alleviates diabetes-associated cognitive dysfunction by suppressing cuproptosis.

Juan Hu, Qiao Li, Shiqiu Jiang, Yingying Deng, Lan Yang, Mengyu Du, Shuxuan He, Fuxing Xu, Chaoying Yan, Wei Gao, Yansong Li, Yaomin Zhu.

  Mitochondrial dysfunction and neuronal impairment are hallmark features of Diabetes-Associated Cognitive Dysfunction (DACD), mitochondrial transplantation is also a therapeutic intervention for DACD. However, the precise mechanism underlying its therapeutic effects are not fully elucidated. Given that imbalances in copper homeostasis and cuproptosis are associated with various neurodegenerative disorders and diabetic myocardial damage, we hypothesize a role for cuproptosis in the pathogenesis of DACD. We further propose that therapeutic peripheral mitochondrial transplantation may ameliorate DACD by reducing processes of cuproptosis. In this research, the study delved into the expression levels of cuproptosis-associated proteins FDX1, LIAS, and DLAT, as well as the copper content in both type 2 diabetes mellitus (T2DM) mice and primary neuronal cells exposed to high glucose and palmitic acid (HG/Pal). Furthermore, the cognitive capabilities of the mice were evaluated using a series of behavioral tests. The findings revealed that in primary neurons exposed to HG/Pal, the expression of copper levels was elevated, and the levels of FDX1, LIAS, and DLAT were reduced. Post-transplantation of platelet-derived mitochondria (Mito-Plt), a significant reversal of these biomarkers was noted, coincident with an improvement in cognitive deficits in T2DM mice. Significantly, the cuproptosis agonist elesclomol (ES) aggravated these alterations. In summary, the findings collectively suggest a causal connection between DACD and the development of cuproptosis in neurons. The use of exogenous Mito-Plt presents a promising therapeutic approach, capable of rescuing neurons from cuproptosis and thereby potentially alleviating DACD.

Keywords:  Cuproptosis; Diabetes-associated cognitive dysfunction (DACD); Mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111245