Mechanisms of Megamitochondria Formation in NASH

尽管非酒精性脂肪性肝炎是美国最常见的代谢性疾病之一， NASH目前不能用任何FDA批准的药物治疗。为了研制出有效的药物 因此，了解NASH的发病机制是非常迫切和必要的。长期以来一直是一个 为什么一些NASH患者在他们的大脑中有非常大的线粒体，称为巨线粒体，这是一个谜。 肝细胞我们的初步研究表明，巨线粒体是NASH发病的关键因素 在NASH的发病机制中，至少20%的NASH患者在其肝细胞中具有巨线粒体。因此，我们认为， 揭示巨线粒体形成的机制有助于为大规模的 部分NASH患者。我们使用饮食诱导的临床前NASH小鼠模型的研究表明， 蛋氨酸和胆碱缺乏（MCD）饮食喂养在他们的肝细胞巨线粒体。 然而，有趣的是，胆碱缺乏（CD）饮食喂养并没有改变线粒体形态， 提示甲硫氨酸缺乏是巨线粒体形成的关键。以前的研究已经表明 甲硫氨酸是膳食必需氨基酸，它的缺乏会引起全身代谢变化， 多个器官甲硫氨酸是核糖体对接和翻译起始所必需的， 是起始密码子。如果这种氨基酸不足，则激活蛋白水解以从现有蛋白质中获得氨基酸 或多肽。上调的蛋白质降解释放大量的游离氨基酸， 用于蛋白质翻译。因为氨基酸主要通过TCA在肝线粒体中降解 在尿素循环中，过量的氨基酸被转运到肝细胞。鉴于这些发现，我们 假设在MCD饮食诱导的模型中会发生全身蛋白水解的升高， 导致肝线粒体氨基酸超载。当甲硫氨酸缺乏时， 肌肉释放大量的氨基酸，因为我们身体的蛋白质的50-75%存在于骨骼肌中。 肌肉.而摄食引起的氨基酸催化剂的激活， 在这个模型中。这些假设将在实验中得到解决，具体如下 目的：1）确定骨骼肌蛋白水解是否因蛋氨酸缺乏而上调，2） 确定升高的肝脏氨基酸催化剂驱动巨线粒体的形成。如果我们的 假设是正确的，这表明骨骼肌和肝脏之间的代谢相互作用 在巨线粒体相关NASH的发病机制中起重要作用。此外，它将展示如何 氨基酸超负荷后的代谢变化影响肝细胞中的线粒体形态。的结果 通过这些发现，将开发具有新靶点的新治疗策略来治疗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.