The role of mitochondrial apoptotic pathway in islet amyloid-induced β-cell death. (1st November 2021)

• Record Type: Journal Article
• Authors: Wong, Helen Y.; Hui, Queenie; Hao, Zhenyue; Warnock, Garth L.; Woo, Minna; Luciani, Dan S.; Marzban, Lucy
• Is Part Of: Molecular and cellular endocrinology. Volume 537(2021)
• Publication Date: 2021-11-01
• Subjects: Islet amyloid -- Amylin -- β-cell apoptosis -- Cytochrome c -- Caspase-9 -- Type 2 diabetes; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2021.111424
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to β-cell death in type 2 diabetes. We previously showed that extracellular hIAPP aggregates promote Fas-mediated β-cell apoptosis. Here, we tested if hIAPP aggregates can trigger the mitochondrial apoptotic pathway (MAP). hIAPP aggregation in Ad-hIAPP transduced INS-1 and human islet β-cells promoted cytochrome c release, caspase-9 activation and apoptosis, which were reduced by Bax inhibitor. Amyloid formation in hIAPP-expressing mouse islets during culture increased caspase-9 activation in β-cells. Ad-hIAPP transduced islets from Cytc KA/KA and BaxBak βDKO mice (models of blocked MAP), had lower caspase-9-positive and apoptotic β-cells than transduced wild-type islets, despite comparable amyloid formation. Blocking Fas (markedly) and Bax or caspase-9 (modestly) reduced β-cell death induced by extracellular hIAPP aggregates. These findings suggest a role for MAP in amyloid-induced β-cell death and a potential strategy to reduce intracellular amyloid β-cell toxicity by blocking cytochrome c apoptotic function. Highlights: Islet amyloid can trigger the mitochondrial apoptotic pathway in β-cells. Intracellular amyloid promotes mitochondrial cytochrome c release and caspase-9 activation. Blocking the apoptotic function of cytochrome c reduces amyloid β-cell toxicity.