Sirt3-Mediated Metabolic Reprogramming Regulates Osteoclast Differentiation Affecting Periodontitis

Aim or purpose: This study aims to elucidate how SIRT3 modulates periodontitis through acetylation-dependent metabolic reprogramming Materials and methods: Periodontitis was induced in C57BL/6 mice via ligature placemen, with SIRT3 expression quantified by qPCR and immunofluorescence. In vitro, bone marrow-derived osteoclasts were treated with LPS or MG132 (proteasome inhibitor), followed by ubiquitination assays (co-immunoprecipitation). We identified SIRT3-interacting proteins through mass spectrometry and validated their status as SIRT3 substrates via acetylation assays. Glycolytic flux and osteoclast differentiation (TRAP staining/Western blot) were assessed, with SIRT3 overexpression rescue experiments performed using lentiviral transduction. Results: In a murine periodontitis model, SIRT3 expression was significantly downregulated in periodontal tissues compared to healthy controls. Mechanistically, LPS stimulation induced ubiquitination-mediated degradation of SIRT3 in osteoclasts, as evidenced by proteasomal inhibition assays.SIRT3 deficiency led to hyperacetylation of its mitochondrial substrates, thereby enhancing glycolysis and driving osteoclast differentiation. Conclusions: SIRT3 deficiency promotes osteoclastogenesis via acetylated substrate-driven glycolysis, positioning SIRT3 as a therapeutic node to halt bone resorption.