bims-mitrat 2025-03-23 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–03–23
six papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

The role of mitochondria transfer in cancer biological behavior, the immune system and therapeutic resistance.
Single-cell RNA sequencing-guided engineering of mitochondrial therapies for intervertebral disc degeneration by regulating mtDNA/SPARC-STING signaling.
Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
Transplantation of viable allogeneic mitochondria protects kidney function in a mouse model of haemorrhagic shock and rhabdomyolysis-induced acute renal injury.
Selenium nanoparticles activate selenoproteins to mitigate septic lung injury through miR-20b-mediated RORγt/STAT3/Th17 axis inhibition and enhanced mitochondrial transfer in BMSCs.
Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration.

J Pharm Anal. 2025 Mar;15(3): 101141

The role of mitochondria transfer in cancer biological behavior, the immune system and therapeutic resistance.

Xintong Lyu, Yangyang Yu, Yuanjun Jiang, Zhiyuan Li, Qiao Qiao.

  Mitochondria play a crucial role as organelles, managing several physiological processes such as redox balance, cell metabolism, and energy synthesis. Initially, the assumption was that mitochondria primarily resided in the host cells and could exclusively transmit from oocytes to offspring by a mechanism known as vertical inheritance of mitochondria. Recent scholarly works, however, suggest that certain cell types transmit their mitochondria to other developmental cell types via a mechanism referred to as intercellular or horizontal mitochondrial transfer. This review details the process of which mitochondria are transferred across cells and explains the impact of mitochondrial transfer between cells on the efficacy and functionality of cancer cells in various cancer forms. Specifically, we review the role of mitochondria transfer in regulating cellular metabolism restoration, excess reactive oxygen species (ROS) generation, proliferation, invasion, metastasis, mitophagy activation, mitochondrial DNA (mtDNA) inheritance, immune system modulation and therapeutic resistance in cancer. Additionally, we highlight the possibility of using intercellular mitochondria transfer as a therapeutic approach to treat cancer and enhance the efficacy of cancer treatments.

Keywords:  Cancer biological behavior; Immune system; Mitochondria transfer; Therapeutic resistance

DOI:  https://doi.org/10.1016/j.jpha.2024.101141
Bioact Mater. 2025 Jun;48 564-582

Single-cell RNA sequencing-guided engineering of mitochondrial therapies for intervertebral disc degeneration by regulating mtDNA/SPARC-STING signaling.

Guoyu Yang, Chenpeng Dong, Zhaoxi Wu, Peng Wu, Cao Yang, Lanlan Li, Jianxiang Zhang, Xinghuo Wu.

  Intervertebral disc degeneration (IVDD) is a leading cause of discogenic low back pain, contributing significantly to global disability and economic burden. Current treatments provide only short-term pain relief without addressing the underlying pathogenesis. Herein we report engineering of biomimetic therapies for IVDD guided by single-cell RNA-sequencing data from human nucleus pulposus tissues, along with validation using animal models. In-depth analyses revealed the critical role of mitochondrial dysfunction in fibrotic phenotype polarization of nucleus pulposus cells (NPCs) during IVDD progression. Consequently, mitochondrial transplantation was proposed as a novel therapeutic strategy. Transplanted exogeneous mitochondria improved mitochondrial quality control in NPCs under pathological conditions, following endocytosis, separate distribution or fusion with endogenous mitochondria, and transfer to neighboring cells by tunneling nanotubes. Correspondingly, intradiscal mitochondrial transplantation significantly delayed puncture-induced IVDD progression in rats, demonstrating efficacy in maintaining mitochondrial homeostasis and alleviating pathological abnormalities. Furthermore, exogenous mitochondria were engineered with a bioactive, mitochondrial-targeting macromolecule to impart anti-oxidative and anti-inflammatory activities. The obtained multi-bioactive biotherapy exhibited significantly enhanced benefits in IVDD treatment, in terms of reversing IVDD progression and restoring structural integrity through the mtDNA/SPARC-STING signaling pathways. Overall, our engineered mitochondrial therapies hold great promise for treating IVDD and other musculoskeletal diseases linked to mitochondrial dysfunction.

Keywords:  Biotherapy; Engineered mitochondria; Inflammation; Intervertebral disc degeneration; STING signaling

DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.036
Cancer Cell. 2025 Mar 18. pii: S1535-6108(25)00081-9. [Epub ahead of print]

Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.

Michael V Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A Rushworth, Jiri Neuzil.

Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.

DOI: https://doi.org/10.1016/j.ccell.2025.03.002
Shock. 2025 Mar 21.

Transplantation of viable allogeneic mitochondria protects kidney function in a mouse model of haemorrhagic shock and rhabdomyolysis-induced acute renal injury.

Yu-Li Pang, Shi-Yuan Fang, Chien-Chi Huang, Ming-Wei Lin, Jun-Neng Roan, Kuen-Jer Tsai, Chen-Fuh Lam.

METHODS: Mice were subjected to acute hemorrhagic shock and rhabdomyolysis through blood withdrawal and intramuscular glycerol injection. Mitochondria (100 μg) were freshly isolated from the soleus muscles of naïve mice. Mitochondria or placebo solution was randomly delivered into arterial catheter 1 hour after the induction of AKI. The mice were euthanised 36 hours later, and blood samples and kidneys were collected for analysis.
RESULTS: IVIS imaging confirmed increased expression of fluorescence-labelled allogeneic mitochondrial accumulation in AKI kidneys. Mitochondrial transplantation significantly decreased the elevated serum levels of urea nitrogen, creatinine and potassium. The protein expression of endogenous antioxidant molecules (Nrf-2, heme oxygenase-1 and superoxide dismutases) was significantly increased. The BAX-to-Bcl-2 ratio and expression of cleaved caspace-3 were also reduced in the mitochondrial-transplanted animals, indicating the attenuation of mitochondrial-mediated apoptosis in the kidney tissues of AKI mice. Histopathological examination confirmed that degrees of renal tubular injury were improved following mitochondrial transplantation.
CONCLUSIONS: Transplantation of freshly isolated mitochondria augments endogenous antioxidant capacity and ameliorates mitochondrial apoptosis in the injured kidney tissues after haemorrhagic shock and rhabdomyolysis-induced AKI. Allogeneic mitochondrial transplantation could be a potential and feasible therapeutic option for prevention and management of AKI secondary to major trauma.

DOI: https://doi.org/10.1097/SHK.0000000000002579
J Nanobiotechnology. 2025 Mar 20. 23(1): 226

Selenium nanoparticles activate selenoproteins to mitigate septic lung injury through miR-20b-mediated RORγt/STAT3/Th17 axis inhibition and enhanced mitochondrial transfer in BMSCs.

Wan-Jie Gu, Feng-Zhi Zhao, Wei Huang, Ming-Gao Zhu, Hai-Yan Huang, Hai-Yan Yin, Tianfeng Chen.

  Sepsis-induced acute lung injury (ALI) remains a critical clinical challenge with complex inflammatory pathogenesis. While bone marrow mesenchymal stem cells (BMSCs) demonstrate therapeutic potential through anti-inflammatory and cytoprotective effects, their age-related functional decline limits clinical utility. This study developed chitosan-functionalized selenium nanoparticles (SeNPs@CS, 100 nm) to rejuvenate BMSCs through miR-20b-mediated selenoprotein biosynthesis. Mechanistic investigations revealed that SeNPs@CS-treated BMSCs exhibited enhanced mitochondrial transfer capacity, delivering functional mitochondria to damaged alveolar epithelial cells (AECII) for cellular repair. Concurrently, miR-20b upregulation suppressed the RORγt/STAT3/Th17 axis, reducing pro-inflammatory Th17 cell differentiation in CD4+ T lymphocytes. The dual-target mechanism integrates immunomodulation via Th17 pathway inhibition with mitochondrial rejuvenation therapy, representing a paradigm-shifting approach for ALI management. These engineered BMSCs mitigated inflammatory markers in murine models, demonstrating superior efficacy to conventional BMSC therapies. Our findings establish SeNPs@CS-modified BMSCs as a novel therapeutic platform combining nanotechnology-enhanced stem cell engineering with precision immunometabolic regulation, providing new avenues for the treatment of sepsis-induced ALI.

Keywords:  Acute lung injury; BMSCs; Mitochondrial transfer; RORγt/STAT3; Selenium; Th17

DOI:  https://doi.org/10.1186/s12951-025-03312-2
Bone Res. 2025 Mar 17. 13(1): 37

Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration.

Xuri Chen, Yunting Zhou, Wenyu Yao, Chenlu Gao, Zhuomin Sha, Junzhi Yi, Jiasheng Wang, Xindi Liu, Chenjie Dai, Yi Zhang, Zhonglin Wu, Xudong Yao, Jing Zhou, Hua Liu, Yishan Chen, Hongwei Ouyang.

Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders. Mitochondrial transplantation serves as a promising clinical therapy. However, its widespread application is hindered by the limited availability of healthy mitochondria, with the dose required reaching up to 109 mitochondria per injection/patient. This necessitates sustainable and tractable approaches for producing high-quality human mitochondria. In this study, we demonstrated a highly efficient mitochondria-producing strategy by manipulating mitobiogenesis and tuning organelle balance in human mesenchymal stem cells (MSCs). Utilizing an optimized culture medium (mito-condition) developed from our established formula, we achieved an 854-fold increase in mitochondria production compared to normal MSC culture within 15 days. These mitochondria were not only significantly expanded but also exhibited superior function both before and after isolation, with ATP production levels reaching 5.71 times that of normal mitochondria. Mechanistically, we revealed activation of the AMPK pathway and the establishment of a novel cellular state ideal for mitochondrial fabrication, characterized by enhanced proliferation and mitobiogenesis while suppressing other energy-consuming activities. Furthermore, the in vivo function of these mitochondria was validated in the mitotherapy in a mouse osteoarthritis model, resulting in significant cartilage regeneration over a 12-week period. Overall, this study presented a new strategy for the off-the-shelf fabrication of human mitochondria and provided insights into the molecular mechanisms governing organelle synthesis.

DOI: https://doi.org/10.1038/s41413-025-00411-6