IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis
Abstract Background Acute liver failure (ALF) is a life-threatening disease, but its pathogenesis is not fully understood. NETosis is a novel mode of cell death. Although the formation of neutrophil extracellular traps (NETs) has been found in various liver diseases, the specific mechanism by which...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Cellular & Molecular Biology Letters |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11658-023-00529-7 |
| _version_ | 1797363121978867712 |
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| author | Yukun Wang Chunxia Shi Jin Guo Danmei Zhang Yanqiong Zhang Long Zhang Zuojiong Gong |
| author_facet | Yukun Wang Chunxia Shi Jin Guo Danmei Zhang Yanqiong Zhang Long Zhang Zuojiong Gong |
| author_sort | Yukun Wang |
| collection | DOAJ |
| description | Abstract Background Acute liver failure (ALF) is a life-threatening disease, but its pathogenesis is not fully understood. NETosis is a novel mode of cell death. Although the formation of neutrophil extracellular traps (NETs) has been found in various liver diseases, the specific mechanism by which NETosis regulates the development of ALF is unclear. In this article, we explore the role and mechanism of NETosis in the pathogenesis of ALF. Methods Clinically, we evaluated NETs-related markers in the liver and peripheral neutrophils of patients with ALF. In in vitro experiments, HL-60 cells were first induced to differentiate into neutrophil-like cells (dHL-60 cells) with dimethyl sulfoxide (DMSO). NETs were formed by inducing dHL-60 cells with PMA. In in vivo experiments, the ALF model in mice was established with LPS/d-gal, and the release of NETs was detected by immunofluorescence staining and western blotting. Finally, the acetylation levels of IDH1 and MDH1 were detected in dHL-60 cells and liver samples by immunoprecipitation. Results Clinically, increased release of NETs in liver tissue was observed in patients with ALF, and NETs formation was detected in neutrophils from patients with liver failure. In dHL-60 cells, mutations at IDH1-K93 and MDH1-K118 deacetylate IDH1 and MDH1, which promotes the formation of NETs. In a mouse model of ALF, deacetylation of IDH1 and MDH1 resulted in NETosis and promoted the progression of acute liver failure. Conclusions Deacetylation of IDH1 and MDH1 reduces their activity and promotes the formation of NETs. This change aggravates the progression of acute liver failure. |
| first_indexed | 2024-03-08T16:16:45Z |
| format | Article |
| id | doaj.art-d0bc5f026e654dafab2689713b14966a |
| institution | Directory Open Access Journal |
| issn | 1689-1392 |
| language | English |
| last_indexed | 2024-03-08T16:16:45Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj.art-d0bc5f026e654dafab2689713b14966a2024-01-07T12:35:48ZengBMCCellular & Molecular Biology Letters1689-13922024-01-0129111610.1186/s11658-023-00529-7IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosisYukun Wang0Chunxia Shi1Jin Guo2Danmei Zhang3Yanqiong Zhang4Long Zhang5Zuojiong Gong6Department of Infectious Diseases, Renmin Hospital of Wuhan UniversityDepartment of Infectious Diseases, Renmin Hospital of Wuhan UniversityDepartment of Infectious Diseases, Renmin Hospital of Wuhan UniversityDepartment of Infectious Diseases, Renmin Hospital of Wuhan UniversityDepartment of Infectious Diseases, Renmin Hospital of Wuhan UniversityDepartment of Infectious Diseases, Renmin Hospital of Wuhan UniversityDepartment of Infectious Diseases, Renmin Hospital of Wuhan UniversityAbstract Background Acute liver failure (ALF) is a life-threatening disease, but its pathogenesis is not fully understood. NETosis is a novel mode of cell death. Although the formation of neutrophil extracellular traps (NETs) has been found in various liver diseases, the specific mechanism by which NETosis regulates the development of ALF is unclear. In this article, we explore the role and mechanism of NETosis in the pathogenesis of ALF. Methods Clinically, we evaluated NETs-related markers in the liver and peripheral neutrophils of patients with ALF. In in vitro experiments, HL-60 cells were first induced to differentiate into neutrophil-like cells (dHL-60 cells) with dimethyl sulfoxide (DMSO). NETs were formed by inducing dHL-60 cells with PMA. In in vivo experiments, the ALF model in mice was established with LPS/d-gal, and the release of NETs was detected by immunofluorescence staining and western blotting. Finally, the acetylation levels of IDH1 and MDH1 were detected in dHL-60 cells and liver samples by immunoprecipitation. Results Clinically, increased release of NETs in liver tissue was observed in patients with ALF, and NETs formation was detected in neutrophils from patients with liver failure. In dHL-60 cells, mutations at IDH1-K93 and MDH1-K118 deacetylate IDH1 and MDH1, which promotes the formation of NETs. In a mouse model of ALF, deacetylation of IDH1 and MDH1 resulted in NETosis and promoted the progression of acute liver failure. Conclusions Deacetylation of IDH1 and MDH1 reduces their activity and promotes the formation of NETs. This change aggravates the progression of acute liver failure.https://doi.org/10.1186/s11658-023-00529-7DeacetylationAcute liver failureNETosis |
| spellingShingle | Yukun Wang Chunxia Shi Jin Guo Danmei Zhang Yanqiong Zhang Long Zhang Zuojiong Gong IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis Cellular & Molecular Biology Letters Deacetylation Acute liver failure NETosis |
| title | IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis |
| title_full | IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis |
| title_fullStr | IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis |
| title_full_unstemmed | IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis |
| title_short | IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis |
| title_sort | idh1 mdh1 deacetylation promotes acute liver failure by regulating netosis |
| topic | Deacetylation Acute liver failure NETosis |
| url | https://doi.org/10.1186/s11658-023-00529-7 |
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