Attenuated <scp>NIX</scp> in impaired mitophagy contributes to exacerbating cellular senescence in experimental periodontitis under hyperglycemic conditions

Premature accumulation of senescent cells results in tissue destruction, and it is one of the potential primary mechanisms underlying the accelerated progression of diabetes and periodontitis. However, whether this characterized phenomenon could account for periodontal pathogenesis under hyperglycemic conditions remains unclear. In this study, we assessed the senescent phenotypic changes in experimental periodontitis under hyperglycemic conditions. Next, we investigated the mitochondrial function and the potential mitophagy pathways in cellular senescence in vitro and in vivo. Our findings showed that significant senescence occurred in the gingival tissues of diabetic periodontitis mice with increased expression of senescence-related protein p21^Cip1 and the senescence-associated secretory phenotype response as well as the decreased expression of NIP3-like protein X (NIX), a mitochondrial receptor. Likewise, we showed that mitochondrial dysfunction (e.g., reduction of mitochondrial membrane potential and accumulation of reactive oxygen species) was attributed to cellular senescence in: human periodontal ligament cells (hPDLCs) through hyperglycemia-induced and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS)-induced oxidative stresses. Notably, the resulting reduced NIX expression was reversed by the use of the mitochondrial reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC), thus correcting the mitochondrial dysfunction. We further verified the expression of inflammatory mediators and senescence-related factors in mice gingival tissues and identified the possible regulatory pathways. Taken together, our work demonstrates the critical role of cellular senescence and mitochondrial dysfunction in periodontal pathogenesis under hyperglycemic conditions. Hence, restoration of mitochondrial function may be a potential novel therapeutic approach to tackling periodontitis in diabetic patients.