Transplantation of AQP1-overexpressing mitochondria attenuates periodontitis-associated bone loss by regulating mitochondria-ER contacts of macrophages.

backgroundPeriodontitis is a chronic inflammatory disease characterized by oxidative stress, immune dysregulation, and progressive alveolar bone loss. Conventional treatments such as mechanical debridement and antimicrobial therapy often fail to reverse bone destruction or restore periodontal homeostasis, underscoring the need for novel therapeutic strategies. Mitochondria have emerged as critical regulators of immune-metabolic signaling, and their genetic modification offers new opportunities for targeted intervention.

resultsThis study explored mitochondria engineered to overexpress aquaporin 1 (ovAQP1-mito) as a therapeutic approach for periodontitis. In vitro, ovAQP1-mito modulated macrophage activity and inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation, suggesting direct immunometabolic effects. In vivo, transplantation of ovAQP1-mito into a ligature-induced mouse model attenuated alveolar bone loss, reduced inflammatory cell infiltration, and preserved periodontal architecture. Mechanistic studies further demonstrated that ovAQP1-mito enhanced SigmaR1 expression, facilitated endoplasmic reticulum-mitochondria communication, and suppressed osteoclastogenic signaling.

conclusionThese findings indicate that ovAQP1-mito exerts dual regulatory effects by mitigating inflammation and bone resorption through ER-mito contacts and immune-metabolic modulation. Such mitochondria-based engineering may represent a promising therapeutic strategy for periodontitis and potentially other inflammatory bone disorders.