Therapeutic restoration of mitochondria–endoplasmic reticulum cross talk for osteoarthritis
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.
Authors
- Jianfeng Yu (ORCID: https://orcid.org/0000-0001-7174-3803)
- Yifan Ma (ORCID: https://orcid.org/0000-0002-9371-4365)
- Xiaowei Xia
- Shiyan Dong (ORCID: https://orcid.org/0000-0003-2912-8895)
- Yijian Zhang
- Zirui He (ORCID: https://orcid.org/0009-0007-0302-0196)
- Yanrun Zhu
- Lili Yu (ORCID: https://orcid.org/0000-0002-4625-3957)
- Chenqi Yu
- Mingzhuang Hou
- Wen Jiang (ORCID: https://orcid.org/0000-0001-9154-633X)
- Yuan Yuan (ORCID: https://orcid.org/0000-0001-7877-3175)
- Yang Liu (ORCID: https://orcid.org/0000-0002-9284-1944)
- Xiaoping Li (ORCID: https://orcid.org/0000-0002-9702-8127)
- Yifan Wang (ORCID: https://orcid.org/0000-0001-7387-0654)
- Yubin Wu
- Lili Sun (ORCID: https://orcid.org/0000-0003-4695-1998)
- Kang Kang (ORCID: https://orcid.org/0000-0003-2856-7829)
- Yingjie Lu
- Yaoge Deng
- Xuesong Zhu
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- East China University of Science and Technology (CN)
- University of Macau (MO)
- Soochow University (CN)
- Suzhou Municipal Hospital (CN)
- First Affiliated Hospital of Soochow University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-09-02
- DOI
- https://doi.org/10.1073/pnas.2426992122
- Citations
- 2
- Primary Topic
- Osteoarthritis Treatment and Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.34
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- University of Texas MD Anderson Cancer Center
- National Key Research and Development Program of China
- Program of Shanghai Academic Research Leader