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

项目总结/摘要 预计到2050年，2型糖尿病（T2 D）将影响三分之一的美国人， 治疗胰岛素抵抗的根本原因：异位脂质积聚。不足 线粒体氧化在T2 D和非酒精性脂肪性肝病（NAFLD）的发病机制中起作用; 然而，人们对其背后的机制知之甚少。关键TCA的钙依赖性 酶（丙酮酸脱氢酶、α-酮戊二酸脱氢酶和异柠檬酸脱氢酶）涉及 线粒体钙作为线粒体代谢的主要调节剂。此外，钙最近 被认为是胰高血糖素诱导的肝线粒体氧化改变的关键介质。近期 线粒体钙单向转运体（MCU）的鉴定引发了人们对线粒体钙转运体的新兴趣。 钙信号，但MCU在介导肥胖相关的代谢功能障碍中的作用还没有被证实。 研究了确定线粒体钙调节肝脏生理学的机制， 代谢对于理解NAFLD和肝胰岛素抵抗的发病机制至关重要， 将MCU确定为新型药物靶点的潜力。 这项工作将有助于阐明肝MCU调节线粒体代谢的机制， 以及这是如何导致NAFLD和肝脏胰岛素抵抗的。核心假设是MCU扮演了一个 通过调节肝内脂解和胰高血糖素诱导的肝细胞内的改变在能量平衡中起关键作用 葡萄糖产生和线粒体氧化。这将解决使用一种新的位置同位素核磁共振 示踪剂分析方法，以直接评估线粒体通量的体内速率。 总之，这项工作将建立MCU在肝胰高血糖素信号传导和肥胖相关的 线粒体功能障碍

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.