The Mitochondrial Calcium Uniporter: Implications for NAFLD and Hepatic Insulin Resistance

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Project Summary/Abstract Type 2 diabetes (T2D) is predicted to impact one third of Americans by the year 2050, yet there are few treatments available to treat the root cause of insulin resistance: ectopic lipid accumulation. Insufficient mitochondrial oxidation plays a role in the pathogenesis of T2D and non-alcoholic fatty liver disease (NAFLD); however, the mechanisms behind this are poorly understood. The calcium-dependent nature of key TCA enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and isocitrate dehydrogenase) implicate mitochondrial calcium as a master regulator of mitochondrial metabolism. Additionally, calcium has recently been implicated as a critical mediator of glucagon-induced alterations in hepatic mitochondrial oxidation. The recent identification of the mitochondrial calcium uniporter (MCU) has sparked a renewed interest in mitochondrial calcium signaling, yet a role for MCU in mediating obesity-associated metabolic dysfunction has not been investigated. Determining the mechanism by which mitochondrial calcium regulates liver physiology and metabolism is critical to understanding the pathogenesis of NAFLD and hepatic insulin resistance, and has the potential to identify MCU as a novel drug target. This work will serve to elucidate the mechanisms by which hepatic MCU regulates mitochondrial metabolism, and how this contributes to NAFLD and hepatic insulin resistance. The central hypothesis is that MCU plays a critical role in energy balance by modulating intrahepatic lipolysis and glucagon-induced alterations in hepatic glucose production and mitochondrial oxidation. This will be addressed using a novel positional isotope NMR tracer analysis method to directly assess in vivo rates of mitochondrial fluxes. Taken together, this work will establish the role of MCU in hepatic glucagon signaling and the obesity-associated mitochondrial dysfunction.