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Mol. Cells 2010; 30(6): 545-549

Published online December 3, 2010

https://doi.org/10.1007/s10059-010-0161-5

© The Korean Society for Molecular and Cellular Biology

ER Stress Is Implicated in Mitochondrial Dysfunction-Induced Apoptosis of Pancreatic Beta Cells

June Woo Lee1,2, Won Ho Kim2, Jiyoung Yeo1, and Myeong Ho Jung1,*

1School of Korean Medicine, Pusan National University, Yangsan 609-735, Korea, 2Division of Metabolic Disease, Department of Biomedical Scienece, National Institute of Health, Seoul 122-701, Korea

Correspondence to : *Correspondence: jung0603@pusan.ac.kr

Received: July 15, 2010; Revised: August 25, 2010; Accepted: October 22, 2010

Abstract

Mitochondrial dysfunction induces apoptosis of pancre-atic β-cells and leads to type 2 diabetes, but the mecha-nism 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-inducedβ-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 (AMPK- K45R) 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 syn-thase (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. Collec-tively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production, resulting in pancreatic β-cells apoptosis.

Keywords AMP-activated protein kinase (AMPK), Apoptosis, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, nitric oxide (NO), pancrea-tic β-cells

Article

Research Article

Mol. Cells 2010; 30(6): 545-549

Published online December 31, 2010 https://doi.org/10.1007/s10059-010-0161-5

Copyright © The Korean Society for Molecular and Cellular Biology.

ER Stress Is Implicated in Mitochondrial Dysfunction-Induced Apoptosis of Pancreatic Beta Cells

June Woo Lee1,2, Won Ho Kim2, Jiyoung Yeo1, and Myeong Ho Jung1,*

1School of Korean Medicine, Pusan National University, Yangsan 609-735, Korea, 2Division of Metabolic Disease, Department of Biomedical Scienece, National Institute of Health, Seoul 122-701, Korea

Correspondence to:*Correspondence: jung0603@pusan.ac.kr

Received: July 15, 2010; Revised: August 25, 2010; Accepted: October 22, 2010

Abstract

Mitochondrial dysfunction induces apoptosis of pancre-atic β-cells and leads to type 2 diabetes, but the mecha-nism 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-inducedβ-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 (AMPK- K45R) 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 syn-thase (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. Collec-tively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production, resulting in pancreatic β-cells apoptosis.

Keywords: AMP-activated protein kinase (AMPK), Apoptosis, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, nitric oxide (NO), pancrea-tic β-cells

Mol. Cells
Nov 30, 2023 Vol.46 No.11, pp. 655~725
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Kim et al. (pp. 710-724) demonstrated that a pathogen-derived Ralstonia pseudosolanacearum type III effector RipL delays flowering time and enhances susceptibility to bacterial infection in Arabidopsis thaliana. Shown is the RipL-expressing Arabidopsis plant, which displays general dampening of the transcriptional program during pathogen infection, grown in long-day conditions.

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