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.