Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration

作者：Xuri Chen, Yunting Zhou, Wenyu Yao, Chenlu Gao, Zhuomin Sha, Junzhi Yi, Jia-Sheng Wang, Xin Liu, Chenjie Dai, Yi Zhang, Zhonglin Wu, Xudong Yao, Jing Zhou, Hua Liu, Yishan Chen, Hongwei Ouyang · 发表于：Bone Research · 年份：2025 · DOI：10.1038/s41413-025-00411-6 · 被引用次数：6 · 研究领域：Mitochondrial Function and Pathology、Autophagy in Disease and Therapy、Mesenchymal stem cell research

Abstract 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 10 9 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...