2. Academic Validation
  3. Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling

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

  • J Clin Transl Hepatol. 2024 Jun 28;12(6):539-550. doi: 10.14218/JCTH.2023.00562.
Xiaohui Xu 1 2,  Jinmei Feng 1 3,  Xin Wang 4,  Xin Zeng 5,  Ying Luo 1,  Xinyu He 1,  Meihua Yang 6,  Tiewei Lv 2,  Zijuan Feng 1,  Liming Bao 7,  Li Zhao 1,  Daochao Huang 1,  Yi Huang 2 8
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China.
  • 2 Department of Cardiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Key Cardiovascular Specialty, Laboratory of Children's Important Organ Development and Diseases of Chongqing Municipal Health Commission, Chongqing, China.
  • 3 Department of Laboratory Medicine, Chongqing Western Hospital, Chongqing, China.
  • 4 Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.
  • 5 Department of Laboratory Medicine, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China.
  • 6 Departments of Neurology, Epilepsy Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA.
  • 7 Department of Clinical Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
  • 8 Departments of Medicine (Oncology), Washington University School of Medicine, St. Louis, MO, USA.
PMID: 38974954 DOI: 10.14218/JCTH.2023.00562
Abstract

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-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB 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-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

Keywords

GRIM19; IL33; Liver fibrosis; NF-кB; NLRP3 inflammasome; Reactive Oxygen Species.

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