CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis
Arsenic in the environment, such as sodium arsenic (NaAsO2), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325000302 |
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| author | Jingyuan Zhang Lu Wang Yang Lu Fei Zheng Xiaoqian Ding Xiaofeng Yao Jie Bai Ningning Wang Guang Yang Tianming Qiu Xiance Sun |
| author_facet | Jingyuan Zhang Lu Wang Yang Lu Fei Zheng Xiaoqian Ding Xiaofeng Yao Jie Bai Ningning Wang Guang Yang Tianming Qiu Xiance Sun |
| author_sort | Jingyuan Zhang |
| collection | DOAJ |
| description | Arsenic in the environment, such as sodium arsenic (NaAsO2), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here, we found that exposure to NaAsO2 had a suppressive effect on the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2) at the protein and gene levels, and overexpression of CISD2 inhibited NaAsO2-induced ferroptosis and NASH. Additionally, administration of NaAsO2 to hepatocytes triggered mitochondrial dysfunction, manifesting as the release of cytochrome c, impairment of the mitochondrial respiratory chain, and reduction in ATP synthesis. However, these adverse effects were alleviated through overexpression of CISD2. Intracellular iron redistribution was induced by overexpression of CISD2 and inhibited NaAsO2-induced ferroptosis. This inhibition was characterized by a reduction in cytoplasmic iron levels and an increase in mitochondrial iron levels. Our study demonstrated that NaAsO2 induced intracellular iron reorganization and mitochondrial dysfunction through CISD2 inhibition, leading to ferroptosis and NASH. This may provide a novel means of treatment of nonalcoholic fatty liver disease triggered by environmental factors. |
| format | Article |
| id | doaj-art-cbf174855c8f4ccda6b8cdd715f428da |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-cbf174855c8f4ccda6b8cdd715f428da2025-01-23T05:26:08ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01289117694CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitisJingyuan Zhang0Lu Wang1Yang Lu2Fei Zheng3Xiaoqian Ding4Xiaofeng Yao5Jie Bai6Ningning Wang7Guang Yang8Tianming Qiu9Xiance Sun10Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Radiology, the Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian 116044, PR ChinaDepartment of Gastrointestinal Cancer, the Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian 116044, PR ChinaDepartment of Gastrointestinal Cancer, the Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian 116044, PR ChinaDepartment of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Public Health Experimental Teaching Center, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Public Health Experimental Teaching Center, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Global Health Research Center, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Correspondence to: Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, Dalian 166044, PR China.Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Global Health Research Center, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Correspondence to: Department of Occupational and Environmental Health, Global Health Research Center, School of Public Health, Dalian Medical University, Dalian 166044, PR China.Arsenic in the environment, such as sodium arsenic (NaAsO2), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here, we found that exposure to NaAsO2 had a suppressive effect on the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2) at the protein and gene levels, and overexpression of CISD2 inhibited NaAsO2-induced ferroptosis and NASH. Additionally, administration of NaAsO2 to hepatocytes triggered mitochondrial dysfunction, manifesting as the release of cytochrome c, impairment of the mitochondrial respiratory chain, and reduction in ATP synthesis. However, these adverse effects were alleviated through overexpression of CISD2. Intracellular iron redistribution was induced by overexpression of CISD2 and inhibited NaAsO2-induced ferroptosis. This inhibition was characterized by a reduction in cytoplasmic iron levels and an increase in mitochondrial iron levels. Our study demonstrated that NaAsO2 induced intracellular iron reorganization and mitochondrial dysfunction through CISD2 inhibition, leading to ferroptosis and NASH. This may provide a novel means of treatment of nonalcoholic fatty liver disease triggered by environmental factors.http://www.sciencedirect.com/science/article/pii/S0147651325000302Sodium arseniteNonalcoholic steatohepatitisFerroptosisCDGSH iron-sulfur domain-containing protein 2 |
| spellingShingle | Jingyuan Zhang Lu Wang Yang Lu Fei Zheng Xiaoqian Ding Xiaofeng Yao Jie Bai Ningning Wang Guang Yang Tianming Qiu Xiance Sun CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis Ecotoxicology and Environmental Safety Sodium arsenite Nonalcoholic steatohepatitis Ferroptosis CDGSH iron-sulfur domain-containing protein 2 |
| title | CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis |
| title_full | CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis |
| title_fullStr | CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis |
| title_full_unstemmed | CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis |
| title_short | CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis |
| title_sort | cisd2 mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic induced nonalcoholic steatohepatitis |
| topic | Sodium arsenite Nonalcoholic steatohepatitis Ferroptosis CDGSH iron-sulfur domain-containing protein 2 |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325000302 |
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