High glucose-induced PRDX3 acetylation contributes to glucotoxicity in pancreatic β-cells: Prevention by Teneligliptin
Free Radical Biology and Medicine , Volume 160, pp 618-629; doi:10.1016/j.freeradbiomed.2020.07.030
Abstract: Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and survival in type 2 diabetes (T2D) due to the low expression level of endogenous antioxidants in the β-cells. Peroxiredoxin-3 (PRDX3) is a mitochondria specific H202 scavenger and protects the cell from mitochondrial damage. However, nothing is known about how glucotoxicity influences PRDX3 function in the pancreatic beta cells. Exposure of rat insulinoma INS-1 cells and human beta cells (1.1B4) to high glucose conditions (30mM) stimulated acetylation of PRDX3 which facilitates its hyper-oxidation causing mitochondrial dysfunction by SIRT1 degradation. SIRT1 deficiency induces beta cell apoptosis via NOX-JNK-p66Shc signalosome activation. Herein we investigated the direct effect of Teneligliptin, a newer DPP-4 inhibitor on beta-cell function and survival in response to high glucose conditions. Teneligliptin treatment enhances SIRT1 stability and activity by USP22, a ubiquitin specific peptidase. Activated SIRT1 prevents high glucose-induced PRDX3 acetylation by SIRT3 resulted in inhibition of PRDX3 hyper-oxidation thereby strengthening the mitochondrial antioxidant defense. Notably, we identify PRDX3 as a novel SIRT3 target and show their physical interaction. Intriguingly, inhibition of SIRT1 activity by EX-527 exacerbated the SIRT3 mediated PRDX3 deacetylation which leads to peroxiredoxin-3 hyper-oxidation and beta-cell apoptosis by the activation of NOX-JNK-p66Shc signalosome. Collectively, our results unveil a novel and first direct effect of high glucose on PRDX3 acetylation on beta-cell dysfunction by impaired antioxidant defense and SIRT1 mediated SIRT3-PRDX3 activation by Teneligliptin suppresses high glucose-mediated mitochondrial dysfunction.
Keywords: Oxidative stress / glucose / mitochondrial dysfunction / Teneligliptin / Dpp-4
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