Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis
Abstract Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06155-7 |
| _version_ | 1797675047545995264 |
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| author | Liyuan Zhang Yue Dong Luxin Zhang Minjun Wang Ye Zhou Kaiwei Jia Suyuan Wang Mu Wang Yunhui Li Shudan Luo Shan Lu Yiwen Fan Dingji Zhang Yingyun Yang Nan Li Yizhi Yu Xuetao Cao Jin Hou |
| author_facet | Liyuan Zhang Yue Dong Luxin Zhang Minjun Wang Ye Zhou Kaiwei Jia Suyuan Wang Mu Wang Yunhui Li Shudan Luo Shan Lu Yiwen Fan Dingji Zhang Yingyun Yang Nan Li Yizhi Yu Xuetao Cao Jin Hou |
| author_sort | Liyuan Zhang |
| collection | DOAJ |
| description | Abstract Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown. Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. Mechanistically, the mitochondrial IRG1 could associate and trap anti-apoptotic MCL-1 to inhibit the interaction between MCL-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis. Thus, the inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC. |
| first_indexed | 2024-03-11T22:08:03Z |
| format | Article |
| id | doaj.art-8b0643ea588b4493b347879a6c25e75c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T22:08:03Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-8b0643ea588b4493b347879a6c25e75c2023-09-24T11:32:48ZengNature Publishing GroupCell Death and Disease2041-48892023-09-0114911110.1038/s41419-023-06155-7Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesisLiyuan Zhang0Yue Dong1Luxin Zhang2Minjun Wang3Ye Zhou4Kaiwei Jia5Suyuan Wang6Mu Wang7Yunhui Li8Shudan Luo9Shan Lu10Yiwen Fan11Dingji Zhang12Yingyun Yang13Nan Li14Yizhi Yu15Xuetao Cao16Jin Hou17National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityDepartment of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityCenter for Immunotherapy, Chinese Academy of Medical SciencesNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityNational Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical UniversityAbstract Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown. Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. Mechanistically, the mitochondrial IRG1 could associate and trap anti-apoptotic MCL-1 to inhibit the interaction between MCL-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis. Thus, the inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC.https://doi.org/10.1038/s41419-023-06155-7 |
| spellingShingle | Liyuan Zhang Yue Dong Luxin Zhang Minjun Wang Ye Zhou Kaiwei Jia Suyuan Wang Mu Wang Yunhui Li Shudan Luo Shan Lu Yiwen Fan Dingji Zhang Yingyun Yang Nan Li Yizhi Yu Xuetao Cao Jin Hou Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis Cell Death and Disease |
| title | Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis |
| title_full | Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis |
| title_fullStr | Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis |
| title_full_unstemmed | Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis |
| title_short | Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis |
| title_sort | mitochondrial irg1 traps mcl 1 to induce hepatocyte apoptosis and promote carcinogenesis |
| url | https://doi.org/10.1038/s41419-023-06155-7 |
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