ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells |
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Authors: | June Woo Lee Won Ho Kim Jiyoung Yeo Myeong Ho Jung |
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Institution: | (1) Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA;(2) Division of Medical Education, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA;(3) Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8127, St. Louis, MO 63110, USA; |
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Abstract: | Mitochondrial dysfunction induces apoptosis of pancreatic β-cells and leads to type 2 diabetes, but the mechanism involved
in this process remains unclear. Chronic endoplasmic reticulum (ER) stress plays a role in the apoptosis of pancreatic β-cells;
therefore, in current study, we investigated the implication of ER stress in mitochondrial dysfunction-induced β-cells apoptosis.
Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, which are mouse
pancreatic β-cells. Impaired mitochondria dysfunction increased ER stress proteins such as p-eIF2α, GRP78 and GRP 94, as well
as ER stress-associated apoptotic factor, CHOP, and activated JNK. AMP-activated protein kinase (AMPK) was also activated
under mitochondria dysfunction by metabolic stress. However, the inhibition of AMPK by treatment with compound C, inhibitor
of AMPK, and overexpression of mutant dominant negative AMPK (AMPKK45R) blocked the induction of ER stress, which was consist-ent
with the decreased β-cell apoptosis and increase of insulin content. Furthermore, mitochondrial dysfunction increased the
expression of the inducible nitric oxide synthase (iNOS) gene and the production of nitric oxide (NO), but NO production was
prevented by compound C and mutant dominant negative AMPK (AMPK-K45R). Moreover, treatment with 1400W, which is an inhibitor
of iNOS, prevented ER stress and apoptosis induced by mitochondrial dysfunction. Treatment of MIN6N8 cells with lipid mixture,
physiological conditions of impaired mitochondria function, activated AMPK, increased NO production and induced ER stress.
Collectively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production,
resulting in pancreatic β-cells apoptosis. |
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