Role Of Pink1 In Regulating Osteoclast Differentiation During Periodontitis

Periodontitis has recently been recognized as an inflammatory disease caused by oxidative stress, with mitochondrial dysfunction being a key factor leading to oxidative stress. This study aimed to explore the contribution and the underlying mechanisms of PTEN-induced kinase 1 (Pink1) in regulating the differentiation and function of osteoclasts during periodontitis. We first validated the negative correlation between Pink1 expression levels and periodontitis/osteoclast differentiation through clinical tissue samples and in vivo/in vitro experiments (approval number: PJ2023-079-001 and 2307051). Subsequently, by constructing a Pink1 knockout (KO) mouse model of periodontitis and employing experimental techniques including qRT-PCR, Western blot (WB), immunofluorescence (IF), transmission electron microscopy (TEM), Seahorse metabolic analysis, and fluorescent probe staining, we systematically elucidated the specific mechanisms through which Pink1 deficiency promotes osteoclast differentiation and functional enhancement. PINK1 expression was significantly downregulated in periodontitis tissues.In the mouse model, alveolar bone destruction worsened over time, correlating with decreased Pink1 levels in osteoclasts and increased osteoclast numbers. Then, RNA sequencing revealed reduced oxidative phosphorylation and upregulated calcium signaling (Calcineurin-NFATc1 pathway) in Pink1-deficient cells. Besides, Pink1 deficiency strengthened MAMs by promoting Mfn2-IP3R-VDAC1 interactions, increasing mitochondrial calcium influx and NFATc1 activation, which underlined that mitophagy was impaired, but MAM-mediated calcium dysregulation drove osteoclast differentiation. Finally, Bcl-XL reversed mitochondrial calcium overload and osteoclast hyperactivation. These findings unveiled that Pink1 was involved in osteoclast differentiation by regulating mitochondrial calcium transport mediated by MAMs, providing new theoretical basis for the pathogenesis and treatment of periodontitis.