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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusion:</i></b> 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.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases

“…538 Notably, the upregulation of PGC-1α by activating the upstream molecule or coactivating the partners, remarkably reverses impaired mitochondrial biogenesis, oxidative stress, and inflammation in osteoarthritis. [539][540][541][542][543][544] Nevertheless, classical drug therapy may be too late to help due to the relatively late diagnosis during the osteoarthritis process. Fortunately, emerging therapies targeting PGC-1α may possess great potential.…”

Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway

“…To observe whether Adenosine 5’-monophosphate-activated protein kinase (AMPK) agonist AICAR (2840, TOCRIS, Bristol, UK) could reverse the effect of AGEs, AGEs+AICAR group and BSA+AICAR group were set. Cells were first treated with AGEs for 24 hours then with 10 μmol/L AICAR for another 24 hours, 18 , 19 to test whether post-AGE AMPK activation leads to normalization of Cx43 and Cx40 expression.…”

Natural compounds protect against the pathogenesis of osteoarthritis by mediating the NRF2/ARE signaling

“…Advanced glycation end products (AGEs) may induce mitochondrial dysfunction in OA chondrocytes. It has been reported that AGEs can induce oxidative stress and chondrocyte apoptosis by down-regulating the AMPKα/Sirt1/PGC-1α signaling ( Yang et al, 2022 ). Collectively, inhibiting redox-sensitive factors implicated in cell death and stimulating antioxidant expression may facilitate chondrocyte survival and promote cartilage integrity ( Figure 1 ).…”