Therapeutic restoration of mitochondria-endoplasmic reticulum cross talk for osteoarthritis

• 成果类型: Article
• 署名作者: Hou, Mingzhuang; Ma, Yifan; Deng, Yaoge; Wu, Yubin; Zhu, Yanrun; Liu, Yang; Li, Xiaoping; Yu, Lili; He, Zirui; Wang, Yifan; Dong, Shiyan; Xia, Xiaowei; Yu, Jianfeng; Yu, Chenqi; Kang, Kang; Lu, Yingjie; Sun, Lili; Kim, Betty Y. S.; Yuan, Yuan; Zhang, Yijian; Jiang, Wen; Zhu, Xuesong
• 署名单位: Soochow University - China; Soochow University - China; University of Texas System; UTMD Anderson Cancer Center; University of Macau; East China University of Science & Technology; East China University of Science & Technology; University of Texas System; UTMD Anderson Cancer Center; Nanjing Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10525
• DOI: 10.1073/pnas.2426992122
• 发表日期: 2025-09-09
• 关键词: fission; metabolism

摘要

Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.