摘要
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 withβ-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.
基金
supported by grants from National Nature Science Foundation of China(82272494,82472452,82402864)
National Key R&D Program of China(2022YFC2502902)
Key Project of Jiangsu Health Commission(K2023079)
Natural Science Foundation of Jiangsu Province(BK20240368)
Basic Research Pilot Project Suzhou(SSD2024062),China Postdoctoral Science Foundation(2024M762313)
Boxi Youth Natural Science Foundation(BXQN2023014)
the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
