Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells
Copper, a vital mineral nutrient, possesses redox qualities that make it both beneficial and toxic to organisms. Excessive environmental copper exposure can result in neurological damage and cognitive decline in humans. Astrocytes, the predominant glial cells in the brain, are particularly vulnerabl...
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Elsevier
2024-10-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324011618 |
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| author | Wei Shi Qian Zhou Lu Lu Ying Zhang Hu Zhang Yuepu Pu Lihong Yin |
| author_facet | Wei Shi Qian Zhou Lu Lu Ying Zhang Hu Zhang Yuepu Pu Lihong Yin |
| author_sort | Wei Shi |
| collection | DOAJ |
| description | Copper, a vital mineral nutrient, possesses redox qualities that make it both beneficial and toxic to organisms. Excessive environmental copper exposure can result in neurological damage and cognitive decline in humans. Astrocytes, the predominant glial cells in the brain, are particularly vulnerable to pollutants, but the mechanism of copper-induced damage to astrocytes remains elusive. The aim of this study was to determine the role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in initiating NLRP3 inflammasome-induced astrocyte pyroptosis and chronic inflammation under conditions of copper overload. Our findings indicated that copper exposure elevated mitochondrial ROS (mtROS) levels, resulting in mitochondrial damage in astrocytes. This damage caused the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cGAS-STING pathway. This activation resulted in interactions between STING and NLRP3 proteins, facilitating the assembly of the NLRP3 inflammasome and inducing pyroptosis. Furthermore, depletion of mtROS mitigated copper-induced mitochondrial damage in astrocytes and reduced mtDNA leakage. Pharmacological inhibition of STING or STING transfection further reversed copper-induced pyroptosis and the inflammatory response. In conclusion, this study demonstrated that the leakage of mtDNA into the cytoplasm and the subsequent activation of the cGAS-STING-NLRP3 pathway may be potential mechanisms underlying copper-induced pyroptosis in astrocytes. These findings provided new insights into the toxicity of copper. |
| format | Article |
| id | doaj-art-72eaedcc42e743f7a7ae7730ef7f6ee2 |
| institution | OA Journals |
| issn | 0147-6513 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-72eaedcc42e743f7a7ae7730ef7f6ee22025-08-20T01:54:45ZengElsevierEcotoxicology and Environmental Safety0147-65132024-10-0128511708510.1016/j.ecoenv.2024.117085Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cellsWei Shi0Qian Zhou1Lu Lu2Ying Zhang3Hu Zhang4Yuepu Pu5Lihong Yin6School of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, ChinaSchool of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, ChinaSchool of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, ChinaSchool of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, ChinaSchool of Public Health, Yangzhou University, Yangzhou 225000, ChinaSchool of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, ChinaSchool of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, Southeast University, Nanjing, Jiangsu 210009, China; Correspondence to: School of Public Health, Southeast University, 87 Dingjiaqiao Street, Nanjing 210009, China.Copper, a vital mineral nutrient, possesses redox qualities that make it both beneficial and toxic to organisms. Excessive environmental copper exposure can result in neurological damage and cognitive decline in humans. Astrocytes, the predominant glial cells in the brain, are particularly vulnerable to pollutants, but the mechanism of copper-induced damage to astrocytes remains elusive. The aim of this study was to determine the role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in initiating NLRP3 inflammasome-induced astrocyte pyroptosis and chronic inflammation under conditions of copper overload. Our findings indicated that copper exposure elevated mitochondrial ROS (mtROS) levels, resulting in mitochondrial damage in astrocytes. This damage caused the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cGAS-STING pathway. This activation resulted in interactions between STING and NLRP3 proteins, facilitating the assembly of the NLRP3 inflammasome and inducing pyroptosis. Furthermore, depletion of mtROS mitigated copper-induced mitochondrial damage in astrocytes and reduced mtDNA leakage. Pharmacological inhibition of STING or STING transfection further reversed copper-induced pyroptosis and the inflammatory response. In conclusion, this study demonstrated that the leakage of mtDNA into the cytoplasm and the subsequent activation of the cGAS-STING-NLRP3 pathway may be potential mechanisms underlying copper-induced pyroptosis in astrocytes. These findings provided new insights into the toxicity of copper.http://www.sciencedirect.com/science/article/pii/S0147651324011618CopperAstrocyteCGAS-STINGPyroptosisNeurotoxicity |
| spellingShingle | Wei Shi Qian Zhou Lu Lu Ying Zhang Hu Zhang Yuepu Pu Lihong Yin Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells Ecotoxicology and Environmental Safety Copper Astrocyte CGAS-STING Pyroptosis Neurotoxicity |
| title | Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells |
| title_full | Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells |
| title_fullStr | Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells |
| title_full_unstemmed | Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells |
| title_short | Copper induced cytosolic escape of mitochondrial DNA and activation of cGAS-STING-NLRP3 pathway-dependent pyroptosis in C8-D1A cells |
| title_sort | copper induced cytosolic escape of mitochondrial dna and activation of cgas sting nlrp3 pathway dependent pyroptosis in c8 d1a cells |
| topic | Copper Astrocyte CGAS-STING Pyroptosis Neurotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324011618 |
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