Mitochondrial oxidative injury: a key player in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. NAFLD is tightly linked to the metabolic syndrome, insulin resistance, and oxidative stress. Globally, its inflammatory form, nonalcoholic steatohepatitis (NASH), has become the main cause of liver-related morbidity and mortality, mainly due to liver cirrhosis and primary liver cancer. One hallmark of NASH is the presence of changes in mitochondrial morphology and function that are accompanied by a blocked flow of electrons in the respiratory chain, which increases formation of mitochondrial reactive oxygen species in a self-perpetuating vicious cycle. Consequences are oxidation of DNA bases and mitochondrial DNA depletion that are coupled with genetic and acquired mitochondrial DNA mutations, all impairing the resynthesis of respiratory chain polypeptides. In general, several maladaptations of pathways that usually maintain energy homeostasis occur with the early and late excess metabolic stress in NAFLD and NASH. We discuss the interplay between hepatocyte mitochondrial stress and inflammatory responses, focusing primarily on events initiated and maintained by mitochondrial free radical-induced damage in NAFLD. Importantly, mitochondrial oxidative stress and dysfunction are modulated by key pharmacological targets that are related to excess production of reactive oxygen species, mitochondrial turnover and the mitochondrial unfolded protein response, mitophagy, and mitochondrial biogenesis. However, the efficacy of such interventions depends on NAFLD/NASH disease stage.