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MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM

  • Cheng Tian
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Xuewen Min
    Affiliations
    Department of Pathology, Jurong People’s Hospital Affiliated to Jiangsu University, 212400, P. R. China
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  • Yongxu Zhao
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Yuchen Wang
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Xiaoshan Wu
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Situn Liu
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Wei Dou
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Tingting Zhou
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Yan Liu
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Rongkui Luo
    Affiliations
    Department of Pathology, Zhongshan Hospital of Fudan University, 200031, P. R. China
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  • Zhigang Li
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Kathy O. Lui
    Affiliations
    Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, PRC
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  • Yu Li
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Ben Zhou
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China
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  • Qiurong Ding
    Correspondence
    Correspondence to:
    Affiliations
    CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China

    Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China

    Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, P. R. China
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Published:August 15, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.017

      Highlights

      • MRG15 levels are elevated in the livers of mice and patients with NASH.
      • Mitochondrial MRG15 interacts with TUFM and controls its proteolytic degradation by mitochondrial ClpXP.
      • The acetylation level of TUFM at the K82 and K91 sites regulates its stability.
      • Blocking liver MRG15 alleviates NASH progression by stabilizing TUFM.

      Background & Aims

      How hepatic steatosis progresses to non-alcoholic steatohepatitis (NASH) is complicated and remains unclear. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) was previously identified as a master nuclear chromatin remodeler in the rhythmic regulation of lipid synthesis gene expression in the liver. Whether it also contributes to the progression from liver steatosis to NASH is unclear.

      Methods

      We adopted 2 different murine NASH models, liver biopsies from patients with NASH, and primary mouse and human hepatocyte cultures for functional examination of MRG15 in NASH progression. Immunoprecipitation-mass spectrometry was applied to identify protein partners of MRG15, and CRISPR targeting was used for gene depletion in liver cells in vivo.

      Results

      The MRG15 level is increased in the livers of humans and mice with NASH. The inflammatory cytokines in NASH livers stabilize MRG15 by increasing its acetylation. Considerable amounts of MRG15 associate with the outer mitochondrial membrane, where it interacts with and deacetylates the mitochondrial Tu translation elongation factor (TUFM). Deacetylated TUFM, especially at the K82 and K91 sites, is subjected to accelerated degradation by the mitochondrial ClpXP protease system. Reduced liver TUFM consequently results in impaired mitophagy, increased oxidative stress and activation of the NLRP3 inflammasome pathway. Blocking MRG15 expression protects the liver from NASH progression by increasing the stability of liver TUFM. Liver samples from patients with NASH also display a clear reduction in TUFM level, which correlates with increased MRG15 expression.

      Conclusion

      Collectively, these findings uncover a mitochondrial MRG15-TUFM regulatory pathway that contributes significantly to progression from simple steatosis to NASH, and which could potentially be targeted to treat NASH.

      Lay summary

      The incidence of non-alcoholic fatty liver disease and its progressive form non-alcoholic steatohepatitis (NASH) is increasing, posing a significant global health challenge. Herein, we have uncovered the importance of the MRG15-TUFM pathway in NASH development. This pathway is active in the mitochondria (energy powerhouse of the cell) and could be targeted for the treatment of NASH.

      Graphical abstract

      Keywords

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