The Molecular Mechanism Of Liver Injury Induced By Loss Of Function Of ERAD System

Endoplasmic reticulum-associated degradation(ERAD)is an important pathway for protein quality monitoring in eukaryotic cells.It is responsible for the recognition,transfer and degradation of misfolded proteins and clearing the accumulation of non-functional proteins in cells.If the misfolded protein in the cell cannot be removed in time,it may cause a series of diseases.According to relevant reports,if ERAD system is functionally deficient,it will cause at least 60 kinds of related diseases,such as Parkinson’s disease,diabetes,Infectious diseases,cancer,etc.Therefore,it can be seen that ERAD system plays an important role in the occurrence and development of major diseases.To investigate the effect of ERAD deficiency on the liver,we established a liver ERAD-deficient mouse model and an ERAD-deficiency hepatocyte model at individual level and cell level,respectively.By analyzing the apparent indicators of mice and the ultrastructural analysis of liver tissue,we found that mice would have severe liver damage and eventually develop into liver cancer.Interestingly,deletion of ERAD also causes damage to mitochondria in hepatocytes,and the degree of damage increases as the mice age.In the ERAD-deficient hepatocyte model,we have demonstrated that the endoplasmic reticulum-mitochondrial interaction and excess inflammatory factor TNFa are two key factors that cause mitochondrial damage.The endoplasmic reticulum stress occurs in ERAD-deficient hepatocytes,which can disrupt the endoplasmic reticulum-mitochondria interaction.This disorder of interaction between ER and mitochondria will drive Ca2+from ER into the mitochondria,leading to an increase in Ca2+and ROS in the mitochondria,which in turn causes mitochondrial damage.The inflammatory factor TNFa is mainly released by KC cells,and excessive TNFa activates the sustained phosphorylation of JNK,leading to further damage of mitochondria.It is well known that mitochondria play an important regulatory role in cell damage and death.Mitochondrial dysfunction causes a decrease in ATP synthesis,resulting in decreased hepatocyte viability.Moreover,severe mitochondrial damage leads to change in mitochondrial membrane permeability,cytochrome c release,and up-regulation of RIPK1,which in turn activates the mitochondrial death pathway and causes hepatocyte death.To make the results more convincing,we used a Ca2+inhibitor(Ru360)at the individual level to inhibit the Ca2+receptor MCU,thereby preventing Ca2+from entering the mitochondria.One month after continuous injection with Ru360,it was found that the liver function of ERAD-deficient mice partially recovered.Treatment with Ru360 at the cellular level also partially restores mitochondrial function and reduces hepatocyte damage and death.In summary,the ERAD system plays a crucial role in maintaining normal liver function.In the liver,mitochondrial damage is the main cause of hepatocyte injury and death caused by ERAD deficiency,mainly caused by the interaction of endoplasmic reticulum-mitochondria interaction and excess inflammatory factor TNFa.This topic provides a good idea for the study of liver injury and even liver cancer and other related diseases,and also provides some potential drug targets for clinical prevention and treatment of liver injury.