IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury
Patients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca2+ overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes c...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1106693/full |
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| author | Zhibing Liu Zhibing Liu Jinru Ma Xulei Zuo Xuesong Zhang Haibo Xie Feng Wang Changhao Wu Jiaxiang Zhang Qixing Zhu Qixing Zhu |
| author_facet | Zhibing Liu Zhibing Liu Jinru Ma Xulei Zuo Xuesong Zhang Haibo Xie Feng Wang Changhao Wu Jiaxiang Zhang Qixing Zhu Qixing Zhu |
| author_sort | Zhibing Liu |
| collection | DOAJ |
| description | Patients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca2+ overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes cytosolic Ca2+ rise and the specific mechanism whereby overloaded Ca2+ induces ferroptosis remain unknown. The purpose of our study was to explore the role of IP3R-dependent mitochondrial dysfunction in C5b-9 mediated ferroptosis in trichloroethylene sensitized kidney. Our results showed that IP3R was activated, and mitochondrial membrane potential was decreased in the renal epithelial cells of trichloroethylene-sensitized mice, and these changes were antagonized by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was reproduced in a C5b-9-attacked HK-2 cell model. Further investigation showed that RNA interference with IP3R not only alleviated C5b-9-induced cytosolic Ca2+ overload and mitochondrial membrane potential loss but also attenuated C5b-9-induced ferroptosis in HK-2 cells. Mechanistically, IP3R-dependent cytosolic Ca2+ overload activated the mitochondrial permeability transition pore, resulting in the loss of mitochondrial membrane potential and ferroptosis of HK-2 cells. Finally, cyclosporin A, a mitochondrial permeability transition pore inhibitor, not only ameliorated IP3R-dependent mitochondrial dysfunction but also blocked C5b-9-induced ferroptosis. Taken together, these results suggest that IP3R-dependent mitochondrial dysfunction plays an important role in trichloroethylene sensitized renal tubular ferroptosis. |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T05:56:32Z |
| publishDate | 2023-06-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-0512fb7eee9544f6bc92858c776c7c8e2023-06-13T04:31:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.11066931106693IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injuryZhibing Liu0Zhibing Liu1Jinru Ma2Xulei Zuo3Xuesong Zhang4Haibo Xie5Feng Wang6Changhao Wu7Jiaxiang Zhang8Qixing Zhu9Qixing Zhu10Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaKey Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, ChinaDepartment of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, ChinaDepartment of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, ChinaDepartment of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, ChinaDepartment of Nephropathy, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaDepartment of Dermatology, Second Hospital of Anhui Medical University, Hefei, Anhui, ChinaSchool of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United KingdomDepartment of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, ChinaDepartment of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, ChinaKey Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, ChinaPatients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca2+ overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes cytosolic Ca2+ rise and the specific mechanism whereby overloaded Ca2+ induces ferroptosis remain unknown. The purpose of our study was to explore the role of IP3R-dependent mitochondrial dysfunction in C5b-9 mediated ferroptosis in trichloroethylene sensitized kidney. Our results showed that IP3R was activated, and mitochondrial membrane potential was decreased in the renal epithelial cells of trichloroethylene-sensitized mice, and these changes were antagonized by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was reproduced in a C5b-9-attacked HK-2 cell model. Further investigation showed that RNA interference with IP3R not only alleviated C5b-9-induced cytosolic Ca2+ overload and mitochondrial membrane potential loss but also attenuated C5b-9-induced ferroptosis in HK-2 cells. Mechanistically, IP3R-dependent cytosolic Ca2+ overload activated the mitochondrial permeability transition pore, resulting in the loss of mitochondrial membrane potential and ferroptosis of HK-2 cells. Finally, cyclosporin A, a mitochondrial permeability transition pore inhibitor, not only ameliorated IP3R-dependent mitochondrial dysfunction but also blocked C5b-9-induced ferroptosis. Taken together, these results suggest that IP3R-dependent mitochondrial dysfunction plays an important role in trichloroethylene sensitized renal tubular ferroptosis.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1106693/fulloccupational medicamentose-like dermatitis due to trichloroethyleneC5b-9IP3Rmitochondrial dysfunctionferroptosis |
| spellingShingle | Zhibing Liu Zhibing Liu Jinru Ma Xulei Zuo Xuesong Zhang Haibo Xie Feng Wang Changhao Wu Jiaxiang Zhang Qixing Zhu Qixing Zhu IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury Frontiers in Immunology occupational medicamentose-like dermatitis due to trichloroethylene C5b-9 IP3R mitochondrial dysfunction ferroptosis |
| title | IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury |
| title_full | IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury |
| title_fullStr | IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury |
| title_full_unstemmed | IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury |
| title_short | IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury |
| title_sort | ip3r dependent mitochondrial dysfunction mediates c5b 9 induced ferroptosis in trichloroethylene caused immune kidney injury |
| topic | occupational medicamentose-like dermatitis due to trichloroethylene C5b-9 IP3R mitochondrial dysfunction ferroptosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1106693/full |
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