SIRT3 alleviates mitochondrial dysfunction and senescence in diabetes-associated periodontitis by deacetylating LRPPRC

Diabetes-associated periodontitis (DP) is recognized as an inflammatory disease that can lead to teeth loss. Uncontrolled chronic low-grade inflammation-induced senescence impairs the stemness of human periodontal stem cells (hPDLSCs). Sirtuin 3 (SIRT3), an NAD⁺-dependent deacetylase, is pivotal in various biological processes and is closely linked to aging and aging-related diseases. This study aims to explore the mechanism of SIRT3- related senescence and osteogenic differentiation of hPDLSCs under DP and explored the novelty therapeutic targets. Our study revealed that SIRT3 expression was markedly inhibited in periodontal ligament stem cells (PDLSCs) stimulated by high glucose and lipopolysaccharide. Both in vitro and in vivo, reduced SIRT3 expression accelerated cell senescence and impaired osteogenic differentiation of hPDLSCs. We demonstrated that SIRT3 binds to and deacetylates leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), thereby modulating senescence. Additionally, we found that LRPPRC regulates senescence by modulating oxidative phosphorylation and oxidative stress. The activation of SIRT3 by honokiol significantly delayed senescence and promoted alveolar bone regeneration in mice after DP. Our findings indicate that the activation of SIRT3 negatively regulates hPDLSCs senescence by deacetylating LRPPRC, suggesting SIRT3 as a promising therapeutic target for DP.