Mechanisms of Megamitochondria Formation in NASH

尽管是美国最常见的代谢性疾病之一，非酒精性脂肪性肝炎 (NASH)目前不能用FDA批准的任何药物治疗。开发出治疗这种疾病的有效药物 因此，迫切需要了解NASH的致病机制。长期以来，它一直是一种 一些NASH患者体内为什么有极大的线粒体，称为巨线粒体 肝细胞。我们的初步研究表明，巨线粒体是NASH的关键因素 NASH的发病机制和至少20%的NASH患者的肝细胞中存在巨线粒体。因此， 揭示巨线粒体的形成机制有利于寻找治疗大细胞肺癌的靶点 部分NASH患者。我们使用饮食诱导的临床前NASH小鼠模型进行的研究表明 蛋氨酸和胆碱缺乏(MCD)饲料喂养在它们的肝细胞中发育出巨线粒体。 然而，有趣的是，缺乏胆碱(CD)的饮食并没有改变线粒体的形态， 提示蛋氨酸缺乏是巨线粒体形成的关键。此前的研究表明， 蛋氨酸是膳食中必需的氨基酸，蛋氨酸缺乏会引起全身代谢变化。 多个器官。蛋氨酸是核糖体对接和翻译启动所必需的，因为蛋氨酸 是起始密码子。如果这种氨基酸不足，蛋白质就会被激活，从现有的蛋白质中获得一种氨基酸。 或多肽。上调的蛋白质降解释放了大量不会被 用于蛋白质翻译。因为氨基酸主要是通过TCA在肝脏线粒体中降解的 在循环和尿素循环中，多余的氨基酸被输送到肝细胞。鉴于这些发现，我们 假设在MCD饮食诱导的模型中会发生系统蛋白分解的升高，这是 导致肝线粒体氨基酸超载。当蛋氨酸缺乏时，骨骼 肌肉释放大量的氨基酸，这是因为我们身体50%-75%的蛋白质存在于骨骼中 肌肉。而摄食引起的氨基酸分解代谢的激活会导致巨线粒体 在这个模型中形成。这些假设将在实验中得到解决，具体如下 目的：1)确定甲硫氨酸缺乏是否上调骨骼肌蛋白分解；2)确定甲硫氨酸缺乏是否上调骨骼肌蛋白分解。 确定肝脏氨基酸分解代谢升高驱动巨线粒体的形成。如果我们的 假设是正确的，这将表明骨骼肌和肝脏之间的代谢相互作用 巨线粒体相关NASH发病机制中的重要作用。此外，它还将展示如何 氨基酸超负荷后的代谢变化影响肝细胞线粒体的形态。由于…… 这些发现，将开发新的治疗策略和新的靶点来治疗NASH患者。

Despite being one of the most prevalent metabolic diseases in the United States, nonalcoholic steatohepatitis (NASH) cannot currently be treated by any FDA-approved medicine. To develop effective drugs for this disease, it is urgent and necessary to understand the pathogenic mechanisms of NASH. It has long been a mystery why some NASH patients have extremely large mitochondria, termed megamitochondria, in their hepatocytes. Our preliminary studies have revealed that megamitochondria is crucial factor for the NASH pathogenesis and at least 20% of NASH patients possess megamitochondria in their hepatocytes. Therefore, uncovering the mechanism of megamitochondria formation benefits in finding therapeutic targets for a large portion of patients with NASH. Our study using a diet-induced preclinical NASH mouse model indicated methionine- and choline-deficient (MCD) diet feeding developed megamitochondria in their hepatocytes. Interestingly, however, choline-deficient (CD) diet feeding did not change mitochondrial morphology, suggesting methionine deficiency is the key to megamitochondria formation. Previous studies have shown that methionine is the dietary essential amino acid and its deficiency causes systemic metabolic changes in multiple organs. Methionine is necessary for ribosomal docking and translational initiation because methionine is the start codon. If this amino acid is insufficient, proteolysis is activated to obtain one from existing proteins or polypeptides. Upregulated protein degradation releases a large number of free amino acids that will not be used for protein translation. Because amino acids are primarily degraded in hepatic mitochondria via the TCA cycle and the Urea cycle, excess amino acids are transported to hepatocytes. Given these findings, we hypothesized that the elevation of systemic proteolysis would occur in the MCD diet-induced model, which leads to the amino acid overload of hepatic mitochondria. When methionine deficiency occurs, the skeletal muscles release a great deal of amino acids, due to the fact that 50-75% of our body's proteins exist in skeletal muscles. And the activation of amino acid catabolism due to diet feeding would cause the megamitochondria formation in this model. These hypotheses will be addressed in the experiments with the following Specific Aims: 1) to determine whether skeletal muscle proteolysis is upregulated by methionine deficiency, and 2) to determine the elevated hepatic amino acid catabolism drives the megamitochondria formation. If our hypothesis is correct, it would suggest that the metabolic interaction between skeletal muscles and livers has significant roles in the pathogenesis of megamitochondria-associated NASH. Moreover, it will demonstrate how metabolic changes after amino acid overload affect mitochondrial morphology in hepatocytes. As a result of these findings, new therapeutic strategies with novel targets will be developed to treat patients with NASH.