Regulation of mitochondrial health in mammalian livers.

Project Summary Chronic liver diseases are common in the human population, including non-alcoholic fatty liver disease and liver failure. These conditions are inherited or acquired due to a number of potential etiologies and can progress to fibrosis, cirrhosis and hepatocellular carcinoma. Therapeutic strategies to limit the incidence and progression of liver disease would be broadly applicable to affected individuals. A common observance in humans and animal models with liver disease is accumulating mitochondrial electron transport chain (ETC) dysfunction, which contributes to disease progression and pathophysiology. Our long-term objective is to identify therapeutic opportunities which promote mitochondrial health in the mammalian liver. Our preliminary data indicate that there are selective processes in animals and humans in vivo which promote the expansion and proliferation of hepatocytes with functional mitochondria, centering around acetyl-CoA production and protection from hepatotoxic challenges. Understanding the biology underlying this processes may provide an opportunity to promote mitochondrial health in the liver. In Aim 1, we will examine the regulation of ETC health in the liver under homeostatic conditions, making use of a collection of conditional knockout alleles in mice which target each component of the mitochondrial ETC. In Aim 2, we will investigate how ETC health is regulated in non-alcoholic fatty liver disease. In Aim 3, we will examine regulation of ETC health following hepatotoxin challenges. In each aim, we will examine the underlying mechanisms as they relate to acetyl-CoA production, which we have found to be a key metabolite regulating proliferation and survival of hepatocytes. Together, these objectives will investigate mechanisms underlying the regulation of mitochondrial health in the mammalian liver in multiple physiologic scenarios, and inform on therapeutic strategies to augment these mechanisms and prevent progression of liver disease.