Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling

作者全名：Xu, Xiaohui; Feng, Jinmei; Wang, Xin; Zeng, Xin; Luo, Ying; He, Xinyu; Yang, Meihua; Lv, Tiewei; Feng, Zijuan; Bao, Liming; Zhao, Li; Huang, Daochao; Huang, Yi

作者地址：[Xu, Xiaohui; Luo, Ying; He, Xinyu; Feng, Zijuan; Zhao, Li; Huang, Daochao] Chongqing Med Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders, Inst Pediat,Minist Educ,Key Lab Child Dev & Disord, Chongqing, Peoples R China; [Xu, Xiaohui; Lv, Tiewei; Huang, Yi] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Cardiol, Childrens Hosp,Minist Educ,Key Lab Child Dev & Dis, Chongqing, Peoples R China; [Feng, Jinmei] Chongqing Western Hosp, Dept Lab Med, Chongqing, Peoples R China; [Wang, Xin] Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing, Peoples R China; [Zeng, Xin] Third Peoples Hosp Chengdu, Dept Lab Med, Chengdu, Sichuan, Peoples R China; [Yang, Meihua] Barnes Jewish Hosp, Epilepsy Ctr, Dept Neurol, St Louis, MO USA; [Yang, Meihua] Washington Univ, Sch Med, St Louis, MO USA; [Bao, Liming] Cornell Univ, Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA; [Huang, Yi] Washington Univ, Dept Med, Sch Med, St Louis, MO USA; [Huang, Yi] Washington Univ, Sch Med, Dept Oncol, St Louis, MO USA; [Huang, Yi] Chongqing Med Univ, Childrens Hosp, 136 Zhongshan Erd Rd, Chongqing 400014, Peoples R China

通信作者：Huang, Y (通讯作者)，Chongqing Med Univ, Childrens Hosp, 136 Zhongshan Erd Rd, Chongqing 400014, Peoples R China.

来源：JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY

ESI学科分类：　

WOS号：WOS:001234456400001

JCR分区：Q2

影响因子：3.1

年份：2024

卷号：12

期号：6

开始页：539

结束页：550

文献类型：Article

关键词：Liver fibrosis; GRIM19; Reactive Oxygen Species; NF-& kcy;B; NLRP3 inflammasome; IL33

摘要：Background and Aims: Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis. Methods: GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo . We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF. Results: Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-& kcy;B activation via an IKK/I & kcy;B partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-& kcy;B pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo . Conclusions: The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-& kcy;B signaling, providing potential therapeutic approaches for earlier HF prevention.

基金机构：National Nature Science Foundation of China [32171119, 32371173]; Ministry of Education Key Laboratory of Child Development and Disorders [GBRP-202116]; Nature Science Foundation of Chongqing Sci-ence and Technology Bureau [CSTB2022NSCQ-MSX0838]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K202100401]; Future Medical Youth Innovation Team Support Project of Chongqing Medical University [W0175]

基金资助正文：This study was partially supported by the National Nature Science Foundation of China [No.32171119; No.32371173] ; the general basic research project from the Ministry of Education Key Laboratory of Child Development and Disorders [GBRP-202116] ; the Nature Science Foundation of Chongqing Sci-ence and Technology Bureau [CSTB2022NSCQ-MSX0838] ; the Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K202100401] ; and the Future Medical Youth Innovation Team Support Project of Chongqing Medical University [W0175] .