Quality Control of Mitochondrial Nutrient Transporters

线粒体营养转运蛋白的质量控制

• 批准号: 9142682
• 负责人: Adam Lucas Hughes
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142682
• 关键词: Amino Acids; Area; Biological Models; Carrier Proteins; Cell membrane; Cells; Development; Diabetes Mellitus; Disease; Excision; Family; Goals; Heme Iron; Inner mitochondrial membrane; Link; Lipids; Lysosomes; Malignant Neoplasms; Mammals; Membrane; Metabolic; Metabolic stress; Metabolism; Mitochondria; Neurodegenerative Disorders; Nutrient; Organelles; Oxidative Phosphorylation; Pathway interactions; Play; Process; Proteins; Quality Control; Reaction; Regulation; Research; Role; Sorting - Cell Movement; Structure; Sulfur; System; Time; Transport Reaction; Vacuole; Wing; Yeasts; amino acid metabolism; combat; insight; mitochondrial dysfunction; programs; response

PROJECT SUMMARY/ABSTRACT Mitochondria are central to cellular metabolism. They produce energy through oxidative phosphorylation, and participate in the metabolism of amino acids, heme, iron-sulfur clusters, lipids, and other essential cellular metabolites. Alteration in mitochondria function is linked to many diseases, including cancer, diabetes, and numerous neurodegenerative disorders. The majority of the biosynthetic reactions mitochondria participate in occur within the matrix of the mitochondria, which is bounded by two membranes: a permeable outer membrane, and an impermeable inner membrane. Cellular metabolites crucial for these reactions are transported across the inner mitochondrial membrane through nutrient carriers, the largest class of which is the mitochondrial carrier family. Despite their central importance in cellular metabolism, very little is understood about how cells regulate the levels of mitochondrial metabolite transporters to control nutrient compartmentalization. Using yeast as a model system, we recently found that mitochondrial function is intimately linked to the cytoplasmic pool of amino acids. Amino acids are typically stored in the vacuole or lysosome at high levels. However, disruption of efficient storage capability of this organelle leads to rapid mitochondrial dysfunction, likely through metabolic overload. We have now uncovered a mitochondrial quality control pathway that specifically and selectively eliminates mitochondrial carrier proteins in response to changes in cellular amino acid pools. Removal of these proteins occurs through a selective intermediate structure called a mitochondrial derived compartment, or MDC. Our current hypothesis is that sequestration of nutrient carriers by this pathway protects mitochondria in times of cellular metabolic stress. Excitingly, this pathway appears to be just one wing of what we are proposing is a global cellular system for regulation of nutrient transporters to control intracellular amino acid levels. In this application, we lay out a long-term goal of our research program: to ultimately understand how cells regulate metabolite transporters to control cellular nutrient compartmentalization. As a first step in this process, we will focus on three areas outlined in this proposal: 1) understanding how mitochondrial nutrient transporters are selectively removed from the mitochondrial inner membrane for destruction in both yeast and mammals; 2) examining how amino acid levels trigger this pathway, and 3) investigating the coordination of the mitochondrial MDC pathway with similar systems that regulate levels of plasma membrane and lysosomal nutrient transporters. Understanding how intracellular metabolites trigger selective removal and destruction of mitochondrial nutrient carriers will provide important insights into mechanisms of intra-organelle protein sorting, and identify new modes of cellular metabolic regulation.

项目总结/摘要 线粒体是细胞代谢的中心。它们通过氧化产生能量 磷酸化，并参与氨基酸，血红素，铁硫簇，脂质等的代谢 必需的细胞代谢物。线粒体功能的改变与许多疾病有关，包括癌症， 糖尿病和许多神经退行性疾病。大多数的生物合成反应线粒体 参与发生在线粒体的基质内，线粒体由两层膜包围：一层是可渗透的， 外膜和不可渗透的内膜。对这些反应至关重要的细胞代谢物是 通过营养载体运输穿过线粒体内膜，其中最大的一类是 线粒体携带者家族尽管它们在细胞代谢中至关重要，但人们对其了解甚少。 关于细胞如何调节线粒体代谢物转运蛋白的水平， 划分使用酵母作为模型系统，我们最近发现线粒体功能是 与细胞质的氨基酸库紧密相连。氨基酸通常储存在液泡中， 高水平的溶酶体。然而，这种细胞器的有效储存能力的破坏导致快速的 线粒体功能障碍，可能是由于代谢过载我们现在发现了一种线粒体 控制途径，特异性和选择性消除线粒体载体蛋白，以响应 细胞氨基酸库的变化。这些蛋白质的去除是通过一种选择性的中间体 一种叫做线粒体衍生区室（mitochondrial derived compartment，MDC）的结构。我们目前的假设是， 通过该途径的营养载体在细胞代谢应激时保护线粒体。令人兴奋的是，这 这条通路似乎只是我们提出的全球细胞系统的一个翅膀， 控制细胞内氨基酸水平的营养转运蛋白。在这个应用程序中，我们制定了一个长期目标， 我们的研究计划：最终了解细胞如何调节代谢物转运蛋白，以控制细胞 营养分区作为这一进程的第一步，我们将重点关注本报告概述的三个领域。 建议：1）了解线粒体营养转运蛋白是如何选择性地从细胞中去除的。 线粒体内膜破坏在酵母和哺乳动物; 2）检查氨基酸水平如何 触发这一途径，和3）研究线粒体MDC途径与类似的 调节质膜和溶酶体营养转运蛋白水平的系统。了解如何 细胞内代谢物触发线粒体营养载体的选择性去除和破坏， 细胞器内蛋白质分选机制的重要见解，并确定新的细胞模式， 代谢调节