α-KG alleviates mitochondrial dysfunction and attenuates HPDLSCs senescence in periodontitis through LKB1-AMPK activation

Feb 25, 2026Cellular signalling

Alpha-Ketoglutarate reduces energy problems and slows aging in gum disease cells by activating the LKB1-AMPK energy control pathway

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Abstract

Treatment with α-ketoglutarate significantly restored mitochondrial function in human periodontal ligament stem cells exposed to inflammation.

Inflammation from lipopolysaccharide exposure led to reduced mitochondrial function and increased cellular senescence in human periodontal ligament stem cells.
α-Ketoglutarate treatment restored mitochondrial homeostasis and enhanced osteogenic differentiation in these stem cells.
The protective effects of α-ketoglutarate were associated with the activation of AMPK signaling, which was crucial for mitigating inflammation-induced dysfunction.
Inhibition of AMPK signaling negated the beneficial effects of α-ketoglutarate on mitochondrial function and cellular senescence.
In a rat model of periodontitis, oral α-ketoglutarate reduced alveolar bone loss and improved periodontal regeneration by restoring AMPK signaling.

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Periodontitis is a chronic inflammatory disease characterized by persistent inflammation that induces senescence and functional impairment of human periodontal ligament stem cells (HPDLSCs), thereby hindering periodontal regeneration. Mitochondrial dysfunction is a key driver of inflammation-induced stem cell senescence. However, the signaling mechanisms remain unclear. In this study, we examined whether α-ketoglutarate (α-KG), a vital intermediate in the tricarboxylic acid cycle, could alleviate mitochondrial dysfunction and restore HPDLSCs function in inflammatory environments. In vitro experiments demonstrated that lipopolysaccharide (LPS) exposure led to a loss of mitochondrial membrane potential, excessive accumulation of mitochondrial reactive oxygen species, cellular senescence, and impaired osteogenic differentiation in HPDLSCs. Treatment with α-KG significantly restored mitochondrial homeostasis, decreased senescence-associated β-galactosidase activity and the expression of P16 and P53, and enhanced osteogenic differentiation. Mechanistically, α-KG markedly activated AMP-activated protein kinase (AMPK) signaling, while pharmacological inhibition of AMPK negated the protective effects of α-KG on mitochondrial function, senescence, and osteogenesis. Further analysis revealed that α-KG restored the expression of liver kinase B1 (LKB1), a key upstream activator of AMPK, establishing an α-KG/LKB1-AMPK signaling axis in the periodontitis inflammatory microenvironment. In a ligature-induced rat model of periodontitis, oral administration of α-KG mitigated alveolar bone loss, reduced the expression of senescence-associated markers, restored AMPK signaling in periodontal tissues, and promoted periodontal regeneration in vivo. Collectively, these findings reveal that AMPK-dependent mitochondrial restoration is a critical mechanism through which α-KG counteracts inflammation-induced HPDLSCs senescence and osteogenic dysfunction, suggesting that α-KG may serve as a promising therapeutic strategy for periodontal regeneration in inflammatory contexts.

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α-KG alleviates mitochondrial dysfunction and attenuates HPDLSCs senescence in periodontitis through LKB1-AMPK activation

Abstract

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