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Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPK[alpha]-SIRT1-PGC-1[alpha] Pathway
Ist Teil von
Pharmacology, 2022-05, Vol.107 (5-6), p.298
Ort / Verlag
S. Karger AG
Erscheinungsjahr
2022
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 (â³[Psi]) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. Results: The results showed that AGEs impaired â³[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. Keywords: Advanced glycation end products, Mitochondrial dysfunction, AMP-activated protein kinase, Sirtuin 1, Peroxisome proliferator-activated receptor gamma coactivator-1[alpha]