Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway
Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic...
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/5/2858 |
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| author | Ching-Yao Yang Shing-Hwa Liu Chin-Chuan Su Kai-Min Fang Tsung-Yuan Yang Jui-Ming Liu Ya-Wen Chen Kai-Chih Chang Haw-Ling Chuang Cheng-Tien Wu Kuan-I Lee Chun-Fa Huang |
| author_facet | Ching-Yao Yang Shing-Hwa Liu Chin-Chuan Su Kai-Min Fang Tsung-Yuan Yang Jui-Ming Liu Ya-Wen Chen Kai-Chih Chang Haw-Ling Chuang Cheng-Tien Wu Kuan-I Lee Chun-Fa Huang |
| author_sort | Ching-Yao Yang |
| collection | DOAJ |
| description | Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic β-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 μM) significantly decreased insulin secretion and cell viability in pancreatic β-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (<i>Bax</i><i>, Bak</i>, <i>p53</i>)/antiapoptotic (<i>Bcl-2</i>) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 μM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant <i>N</i>-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 μM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 μM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to β-cell death. |
| first_indexed | 2024-03-09T20:35:56Z |
| format | Article |
| id | doaj.art-6250c9286c3e4fb2b92ba31b06b91647 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:35:56Z |
| publishDate | 2022-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6250c9286c3e4fb2b92ba31b06b916472023-11-23T23:10:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01235285810.3390/ijms23052858Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling PathwayChing-Yao Yang0Shing-Hwa Liu1Chin-Chuan Su2Kai-Min Fang3Tsung-Yuan Yang4Jui-Ming Liu5Ya-Wen Chen6Kai-Chih Chang7Haw-Ling Chuang8Cheng-Tien Wu9Kuan-I Lee10Chun-Fa Huang11Department of Surgery, National Taiwan University Hospital, Taipei 100, TaiwanInstitute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, TaiwanDepartment of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County 500, TaiwanDepartment of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, TaiwanDepartment of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, TaiwanDepartment of Urology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, TaiwanDepartment of Physiology, School of Medicine, College of Medicine, China Medical University, Taichung 404, TaiwanCenter for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, TaiwanDepartment of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, TaiwanDepartment of Nutrition and Master Program of Food and Drug Safety, China Medical University, Taichung 40402, TaiwanDepartment of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, TaiwanSchool of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, TaiwanMethylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic β-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 μM) significantly decreased insulin secretion and cell viability in pancreatic β-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (<i>Bax</i><i>, Bak</i>, <i>p53</i>)/antiapoptotic (<i>Bcl-2</i>) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 μM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant <i>N</i>-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 μM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 μM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to β-cell death.https://www.mdpi.com/1422-0067/23/5/2858methylmercurypancreatic β-cellsapoptosisER stressc-Jun N-terminal kinase (JNK)oxidative stress |
| spellingShingle | Ching-Yao Yang Shing-Hwa Liu Chin-Chuan Su Kai-Min Fang Tsung-Yuan Yang Jui-Ming Liu Ya-Wen Chen Kai-Chih Chang Haw-Ling Chuang Cheng-Tien Wu Kuan-I Lee Chun-Fa Huang Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway International Journal of Molecular Sciences methylmercury pancreatic β-cells apoptosis ER stress c-Jun N-terminal kinase (JNK) oxidative stress |
| title | Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway |
| title_full | Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway |
| title_fullStr | Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway |
| title_full_unstemmed | Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway |
| title_short | Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway |
| title_sort | methylmercury induces mitochondria and endoplasmic reticulum stress dependent pancreatic β cell apoptosis via an oxidative stress mediated jnk signaling pathway |
| topic | methylmercury pancreatic β-cells apoptosis ER stress c-Jun N-terminal kinase (JNK) oxidative stress |
| url | https://www.mdpi.com/1422-0067/23/5/2858 |
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