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

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-1 alpha (PGC-1 alpha) 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 AMPK alpha/SIRT1/PGC-1 alpha. Methods: We knocked down or overexpressed AMPK alpha, SIRT1, and PGC-1 alpha by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (delta Psi) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. Results: The results showed that AGEs impaired delta Psi, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPK alpha, SIRT1, and PGC-1 alpha expression in chondrocyte. AMPK alpha pharmacologic activation or overexpression of AMPK alpha, SIRT1, and PGC-1 alpha reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPK alpha activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1 alpha-siRNA chondrocyte. Conclusion: Taken together, AGEs reduced the AMPK alpha/SIRT1/PGC-1 alpha signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis. These results indicated that target AMPK may be as a novel therapeutic strategy for AGEs-related OA prevention.& nbsp;(c)& nbsp;2022 S. Karger AG, Base

Automated summary

In this study, it was found that AGEs reduced AMPK alpha/SIRT1/PGC-1 alpha signaling in chondrocytes, leading to mitochondrial dysfunction and increased oxidative stress, inflammation, and apoptosis. Activation or overexpression of AMPK alpha, SIRT1, and PGC-1 alpha reversed the impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes.