The role of mitochondrial ATP production in liver failure

PROJECT SUMMARY/ABSTRACT Mitochondrial energetic dysfunction is implicated in many common human diseases, including conditions impacting the liver such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver failure. The precise consequences of loss of mitochondrial energetics in the mammalian liver are largely unknown. To date our understanding of the roles of mitochondrial complex V (mCV), or ATP synthase, has arisen primarily from in vitro cultured cells or yeast studies. These seminal results revealed structural and functional insights into mCV’s role, but are unable to clearly delineate the physiologic effects of mitochondrial energy dysfunction. Our lab has developed a new mouse model that conditionally deletes a core subunit of mCV and ablates the ATP synthesis activity of the mitochondria. This model will enable us to study pure mitochondrial energy dysfunction in any organ system, and in particular this proposal aims to determine effects of mitochondrial energy dysfunction in the adult murine liver. To accomplish this, a combination of isotope tracing mass spectrometry, nuclear magnetic resonance, specialized mitochondrial respiratory assays, electron microscopy, next generation sequencing and mouse physiology studies will be used. The specific aims of this proposal intend to 1) understand the mitochondrial structural and functional consequences of mCV disruption in liver and 2) determine the contributions of mitochondrial ATP to liver and whole body homeostasis. The findings of this proposal will provide insights into basic mitochondrial biology and the pathophysiology of common liver diseases.