Role of the mitochondrial protein MCJ in the development of non-alcoholic fatty liver disease (NAFLD)

Abstract

[EN] Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western world, affecting 20-30% of the general population. NAFLD comprises a broad range of clinical disorders from pure steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. However, the molecular mechanisms underlying NAFLD progression are not completely understood and the tools for its early diagnosis are limited. Notably, mitochondrial alterations have been described in a variety of chronic liver diseases, including NAFLD. Recently, MCJ, an inner mitochondrial membrane protein, has emerged as the first endogenous inhibitor of the electron transport chain complex I. In this project, we studied the role of MCJ in the pathogenesis of NAFLD and investigated the effect that the absence of MCJ exerts in the progression of the disease. Interestingly, we found that MCJ expression is increased during NAFLD. Moreover, MCJ silencing protected against hepatic lipid accumulation, liver injury and inflammation in the methionine-choline deficient mouse model of NASH. Apparently, loss of MCJ led to increased fatty acid β- oxidation, Krebs cycle function, and glycolysis rate, which maintained mitochondrial respiration and ATP production through oxidative phosphorylation. In other words, these metabolic adaptations were able to counteract the cytotoxic effects of fat accumulation on mitochondria and ultimately on hepatocytes. Altogether, MCJ arises as a key regulator of NAFLD paving the way for new promising therapeutic approaches.