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

How hepatic steatosis progresses to nonalcoholic steatohepatitis (NASH) is complicated and remains elusive. 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 liver. Whether it also contributes to the progression from liver steatosis to NASH is unclear.

Qiurong Ding,scientist from Shanghai Institute of Nutrition and Health,and her team adopted two 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. The immunoprecipitation-mass spectrometry (IP-MS) was applied to identify protein partners of MRG15, and CRISPR targeting was used for gene depletion in liver cells in vivo.

The MRG15 level is increased in the livers of humans and mice with NASH. The inflammatory cytokines in NASH liver stabilize MRG15 via increasing its acetylation. Considerable amount of MRG15 is further identified to associate with the outer mitochondrial membrane, where it interacts with and deacetylates the mitochondrial Tu translation elongation factor (TUFM). Deacetylated TUFM, especially at the 82K and 91K sites, is subjected to accelerated degradation by the mitochondrial ClpXP protease system. Reduced liver TUFM consequently results in impaired mitophagy, increased oxidative stress and activated NLRP3 inflammasome pathway. Blocking MRG15 expression significantly protects the liver from NASH progression via increased stability of liver TUFM. Liver samples from NASH patients also display a clear reduction in TUFM level, in correlation with increased MRG15 expression.

Collectively, these findings uncover a mitochondrial MRG15-TUFM regulation pathway that contributes significantly to the liver progression from simple steatosis to NASH, and a potential target to treat NASH.

This study demonstrates that the mortality factor 4-like protein 1 (MORF4L1, also called MRG15) contributes significantly to the progression from liver steatosis to nonalcoholic steatohepatitis (NASH). Blocking liver MRG15 expression ameliorates NASH progression through stabilizing the mitochondrial Tu translation elongation factor (TUFM) and enhancing mitophagy.

 

Sherry