Advanced glycation end products induces mitochondrial dysfunction via downregulating AMPK/PGC-1α/ SIRT3 signaling pathway in chondrocytes

AimTo investigate the impact of advanced glycation end products (AGEs)on mitochon-drial function in both animal model and chondrocytes, and to explore whether these effects are mediated through the inhibition of the AMPK/PGC- 1α/SIRT3 signaling pathway.MethodsAGEs were administered via intra-articular injection in mice. Osteoarthritis-like lesions in knee joints were assessed using safranin O-fast green staining. Mitochondrial membrane potential (ΔΨm) was evaluated using the JC-1 assay. The expression levels of adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), sirtuin 3 (SIRT3), matrix metalloproteinase (MMP)-3, and MMP-13 were measured by Western blot.ResultsIntra-articular injection of AGEs induced osteoarthritis-like pathological changes in mice after 8 weeks. AGEs significantly impaired mitochondrial function, accompanied by reduced phosphorylation of AMPK and decreased expression of SIRT3 and PGC-1α. Treatment with the selective AMPK agonist AICAR mitigated AGEs-induced mitochondrial damage; however, these protective effects were abolished in SIRT3-knockout or PGC-1 α-knockout chondrocytes.ConclusionsAGEs induce mitochondrial dysfunction in chondrocytes by downregulating the AMPK- PGC-1α -SIRT3 signaling pathway, thereby promoting the progression of osteoarthritis.