image: Mc-mitochondria exhibit superior performance for in vivo mitotherapy. a Schematic illustration of the establishment of the mouse OA model and the experimental design to evaluate the value of mitochondrial amplification for in vivo applications. b Safranin-O/Fast green staining of joint sections at 12 weeks. Scale bar, 50 μm. c Modified and maximum OARSI scoring system (sample = 6 for each group). d Immunohistochemical staining (COL2, ACAN) of joint sections at 12 weeks. Scale bar, 50 μm. e Quantification of COL2 and ACAN in cartilage tissues at 12 weeks (sample = 6 for each group). All data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. P values were determined using one-way ANOVA (c, e). OARSI Osteoarthritis Research Society International.
Credit: Bone Research
Scientists have unveiled a revolutionary method for mass-producing high-quality human mitochondria, potentially transforming treatments for degenerative diseases. By refining stem cell culture conditions, researchers achieved an extraordinary 854-fold increase in mitochondrial production while significantly enhancing energy output. These engineered mitochondria exhibited remarkable therapeutic benefits, notably accelerating cartilage regeneration in osteoarthritis models. This breakthrough addresses a long-standing bottleneck in mitochondrial transplantation, which has been constrained by limited supply and inconsistent quality. Beyond its clinical implications, the study sheds new light on cellular energy dynamics, revealing how cells can be reprogrammed to prioritize mitochondrial synthesis. The innovation paves the way for novel treatments targeting a wide spectrum of mitochondrial dysfunction-related diseases, from joint degeneration to cardiovascular disorders.
Mitochondrial dysfunction is a common denominator in numerous diseases, including osteoarthritis, heart failure, and metabolic disorders. While mitochondrial transplantation has emerged as a promising avenue for restoring tissue function, its clinical potential has been severely hampered by the scarcity of viable mitochondria. Current methods rely on extracting mitochondria from donor tissues, yielding only limited quantities with variable quality, sufficient for a single treatment at best. Moreover, the intricate structure of mitochondria makes synthetic production an enormous challenge. Given the immense demand—up to one billion mitochondria per patient—existing approaches fall far short of therapeutic needs. Recognizing these limitations, researchers sought a sustainable and scalable solution for producing high-quality mitochondria suitable for clinical applications.
Published (DOI: 10.1038/s41413-025-00411-6) on March 17, 2025, in Bone Research, a team from Zhejiang University School of Medicine has pioneered a stem cell-based system that functions as a "mitochondria factory". By leveraging human mesenchymal stem cells and a specially designed culture medium dubbed "mito-condition", the team achieved unparalleled increases in both mitochondrial quantity and quality. These mitochondria exhibited exceptional energy production and facilitated cartilage regeneration in osteoarthritis models. This groundbreaking approach not only overcomes key barriers in mitochondrial transplantation but also deepens our understanding of cellular organelle regulation, opening new frontiers in regenerative medicine.
At the heart of the breakthrough is the innovative "mito-condition" culture medium, which integrates nine essential components, including growth factors and human platelet lysate, to optimize mitochondrial production. Within just 15 days, this method generated 854 times more mitochondria than conventional approaches, all while preserving stem cell viability. The manufactured mitochondria displayed extraordinary functionality, producing 5.7 times more ATP than naturally occurring mitochondria and maintaining stable performance even post-isolation. Mechanistic studies revealed that the mito-condition medium activates the AMPK pathway, a crucial cellular energy sensor, driving upregulation of mitochondrial biogenesis genes such as TFAM. Remarkably, cells undergoing this process downregulated energy-intensive activities like autophagy and secretion, effectively prioritizing mitochondrial synthesis. Transmission electron microscopy confirmed the unique characteristics of these lab-grown mitochondria, which appeared in a distinct rounded form and were significantly more abundant than their native counterparts.
In osteoarthritis models, transplantation of these enhanced mitochondria resulted in substantial cartilage repair over a 12-week period, surpassing the efficacy of traditional mitochondrial treatments. Furthermore, the mitochondria demonstrated impressive storage stability, retaining function for 24 hours at 4°C—a critical factor for real-world clinical applications. The concept of organelle tuning, as demonstrated in this study, could potentially be adapted to generate other cellular components, broadening the horizons of cell engineering and therapeutic applications.
"This work represents a paradigm shift in our ability to produce therapeutic mitochondria," stated corresponding author Dr. Hongwei Ouyang. "By reprogramming stem cells into highly efficient mitochondrial factories, we have solved the critical supply issue that has hindered clinical applications. The mito-condition medium not only amplifies mitochondrial production but also enhances their quality, which directly translates to superior therapeutic outcomes. This platform has the potential to revolutionize treatment strategies for a host of degenerative diseases driven by mitochondrial dysfunction."
The most immediate application of this technology lies in osteoarthritis treatment, where it offers a promising regenerative solution. However, its impact extends far beyond joint disorders, with potential benefits for conditions such as heart disease, neurodegenerative disorders, and wound healing. By enabling the large-scale production of standardized, high-quality mitochondria, this breakthrough could transition mitochondrial transplantation from an experimental concept to a widely accessible clinical therapy. Moreover, the organelle-tuning approach introduced in this study may serve as a blueprint for generating other specialized cellular components, unlocking new possibilities in cell-based medicine. While challenges remain in refining delivery mechanisms and assessing long-term effects, this breakthrough represents a significant leap forward in regenerative science, offering renewed hope for millions suffering from mitochondrial-related diseases.
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References
DOI
Original Source URL
https://doi.org/10.1038/s41413-025-00411-6
Funding information
This work was supported by the National Key Research and Development Program of China (2022YFA1106800) and the National Natural Science Foundation of China (T2121004, 82394441, 92268203).
About Bone Research
Bone Research was founded in 2013. As a new English-language periodical, Bone Research focuses on basic and clinical aspects of bone biology, pathophysiology and regeneration, and supports the foremost discoveries resulting from basic investigations and clinical research related to bone. The aim of the Journal is to foster the worldwide dissemination of research in bone-related physiology, pathology, diseases and treatment.
Journal
Bone Research
Subject of Research
Not applicable
Article Title
Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration
Article Publication Date
17-Mar-2025
COI Statement
The authors declare that they have no competing interests.