Mitochondria replenishment enhances senescent periodontal ligament stem cell osteogenesis and facilitates bone repair

Aging is characterized by the progressive accumulation of molecular and cellular damage, leading to disrupted bone homeostasis and reduced osteogenic potential. Mitochondrial dysfunction, a hallmark of aging, results in elevated reactive oxygen species levels and reduced mitochondrial membrane potential, which significantly impairs osteogenesis of osteoprogenitors cells. Inspired by the naturally occurring intercellular mitochondria transfer during tissue healing process, which activates and enhances cellular reparative functions, this study investigated whether mitochondria replenishment could restore osteogenic capacity of aged human periodontal ligament stem cells (hPDLSCs) and promote bone defect repair. Our findings demonstrate that mitochondria replenishment effectively restores mitochondrial function, enhances osteogenic differentiation of aged hPDLSCs, as well as facilitates bone defect repair in vivo. Mechanistically, mitochondria supplementation upregulates the mitochondrial anchoring protein A-kinase anchoring protein 1 (AKAP1) and activates the cAMP/PKA signaling pathway in mitochondria-receipient hPDLSCs. This study underscores the therapeutic potential of mitochondrial supplementation in reversing aging-related impairments in hPDLSCs and identifies the AKAP1-regulated cAMP/PKA pathway as a key mechanism. These findings offer a promising strategy for overcoming aging-associated challenges in bone regeneration.