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

Mar 3, 2022Pharmacology

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Abstract

Advanced glycation end products (AGEs) reduced mitochondrial function by impairing key regulatory proteins in chondrocytes.

AGEs are associated with impaired mitochondrial membrane potential, intracellular ATP levels, and mitochondrial DNA content.
Decreased expression of AMPKα, SIRT1, and PGC-1α was observed in chondrocytes exposed to AGEs.
Activation or overexpression of AMPKα, SIRT1, and PGC-1α may reverse mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis in AGEs-treated chondrocytes.
Reduced AMPKα/SIRT1/PGC-1α signaling could contribute to increased oxidative stress and inflammation in osteoarthritis.
Targeting AMPK may represent a novel therapeutic strategy for preventing AGEs-related osteoarthritis.

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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 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.

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

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