2. Academic Validation
  3. SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch

SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch

  • Bone Res. 2025 Mar 14;13(1):36. doi: 10.1038/s41413-025-00413-4.
Yaoge Deng # 1 2,  Mingzhuang Hou # 1 2,  Yubin Wu # 1 2,  Yang Liu 1 2,  Xiaowei Xia 1 2,  Chenqi Yu 1 2,  Jianfeng Yu 1 2,  Huilin Yang 3 4,  Yijian Zhang 5 6,  Xuesong Zhu 7 8
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
  • 2 Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China.
  • 3 Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China. suzhouspine@163.com.
  • 4 Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China. suzhouspine@163.com.
  • 5 Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China. zhangyijian@suda.edu.cn.
  • 6 Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China. zhangyijian@suda.edu.cn.
  • 7 Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China. zhuxs@suda.edu.cn.
  • 8 Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China. zhuxs@suda.edu.cn.
  • # Contributed equally.
PMID: 40087281 DOI: 10.1038/s41413-025-00413-4
Abstract

Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis (OA). However, the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive. In this study, we demonstrated mitochondrial damage and aberrant Mitophagy in OA chondrocytes. Genetically overexpressing PTEN-induced putative kinase 1 (PINK1) protects against cartilage degeneration by removing defective mitochondria. PINK1 knockout aggravated cartilage damage due to impaired Mitophagy. SIRT3 directly deacetylated PINK1 to promote Mitophagy and cartilage anabolism. Specifically, PINK1 phosphorylated PKM2 at the Ser127 site, preserving its active tetrameric form. This inhibited nuclear translocation and the interaction with β-catenin, resulting in a metabolic shift and increased energy production. Finally, a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions. Overall, this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.

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