ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells

作者：Lee June Woo; Kim Won Ho; Yeo Jiyoung; Jung Myeong Ho^*

来源：Molecules and Cells, 2010, 30(6): 545-549.

DOI：10.1007/s10059-010-0161-5

• AMP-activated protein kinase (AMPK)
• Apoptosis
• endoplasmic reticulum (ER) stress
• mitochondrial dysfunction
• nitric oxide (NO)
• pancreatic beta-cells

Mitochondrial dysfunction induces apoptosis of pancreatic beta-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 beta-cells; therefore, in current study, we investigated the implication of ER stress in mitochondrial dysfunction-induced beta-cells apoptosis. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, which are mouse pancreatic beta-cells. Impaired mitochondria dysfunction increased ER stress proteins such as p-eIF2 alpha, 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 beta-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 beta-cells apoptosis.

• 出版日期2010-12