Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.
Keywords: Cisd2; aging; lipid metabolism; mitochondria; non-alcoholic fatty liver disease; protein homeostasis.