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This study aims to investigate the role of mitochondrial deacetylation reaction and investigate the mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation with the severity of OA in both human arthritic cartilage and mice inflammatory chondrocytes. Global SIRT3\u00a0deletion accelerates pathological phenotype in post\u2010traumatic OA mice, as evidenced by cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1\u00a0polarization. Mechanistically, SIRT3\u00a0prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis at the post\u2010translational level. The activation of SIRT3\u00a0by honokiol restores cartilage metabolic equilibrium and protects mice from the development of post\u2010traumatic OA. Collectively, the loss of mitochondrial SIRT3\u00a0is essential for the development of OA, whereas SIRT3\u2010mediated proteins deacetylation of COX4I2\u00a0rescues OA\u2010impaired mitochondrial respiratory chain functions to improve the OA phenotype. Herein, the induction of SIRT3\u00a0provides a novel therapeutic candidate for OA treatment.<\/jats:p>","DOI":"10.1002\/advs.202206144","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:02:23Z","timestamp":1674432143000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3\u2010COX4I2 Axis Attenuates Osteoarthritis Progression"],"prefix":"10.1002","volume":"10","author":[{"given":"Yijian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The First Affiliated Hospital of Soochow University Soochow University  Suzhou 215006 China"},{"name":"Orthopaedic Institute Medical College Soochow University  Suzhou 215007 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of 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