Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

作者：Qingshan Yang, Yucong Shi, Tao Jin, Bowen Duan, Shujin Wu · 发表于：Pharmacology · 年份：2022 · DOI：10.1159/000521720 · 被引用次数：26 · 研究领域：Osteoarthritis Treatment and Mechanisms、Advanced Glycation End Products research、Adipose Tissue and Metabolism

INTRODUCTION: Our previous studies have demonstrated advanced glycation end products (AGEs) was an important mediator in osteoarthritis (OA) which may induce mitochondrial dysfunction. AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and its downstream target peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are the critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in OA. This study was designed to test whether AGEs caused mitochondrial dysfunction through modulation of AMPKα/SIRT1/PGC-1α. METHODS: We knocked down or overexpressed AMPKα, SIRT1, and PGC-1α by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (△Ψ) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. RESULTS: The results showed that AGEs impaired △Ψ, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPKα, SIRT1, and PGC-1α expression in chondrocyte. AMPKα pharmacologic activation or overexpression of AMPKα, SIRT1, and PGC-1α reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPKα activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1α-siRNA chondrocyte. CONCLUSION: Taken together, AGEs reduced the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunct...