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.

项目摘要/摘要 线粒体是细胞代谢的核心。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，脂质和其他的代谢 必需的细胞代谢物。线粒体功能的改变与包括癌症在内的许多疾病有关 糖尿病和许多神经退行性疾病。大多数生物合成反应线粒体 参加的线粒体矩阵内发生，这是由两个膜界的：一个可渗透的 外膜和不可渗透的内膜。这些反应至关重要的细胞代谢产物是 通过营养载体在线粒体内部膜上运输，其中最大的类是 线粒体载体家族。尽管它们在细胞代谢中的重要性，但很少被理解 关于细胞如何调节线粒体代谢物转运蛋白的水平以控制营养 分隔。使用酵母作为模型系统，我们最近发现线粒体功能是 与氨基酸的细胞质池密切相关。氨基酸通常存储在液泡中或 高水平的溶酶体。但是，该细胞器的有效存储能力的破坏会导致快速 线粒体功能障碍，可能通过代谢过载。我们现在已经发现了线粒体质量 控制途径，专门和选择性地消除了线粒体载体蛋白的反应 细胞氨基酸池的变化。去除这些蛋白质是通过选择性中间体发生的 结构称为线粒体衍生的隔室或MDC。我们目前的假设是 该途径的营养载体可以在细胞代谢应激时保护线粒体。令人兴奋的是，这个 途径似乎只是我们提出的一个翼是一个全球蜂窝系统，用于调节 营养转运蛋白以控制细胞内氨基酸水平。在此应用中，我们规定了一个长期目标 我们的研究计划：最终了解细胞如何调节代谢物转运蛋白控制细胞 营养区室化。作为此过程的第一步，我们将重点关注此概述的三个领域 提案：1）了解如何选择性地将线粒体营养转运蛋白从 线粒体内膜，用于酵母和哺乳动物的破坏； 2）检查氨基酸如何水平 触发此途径，3）研究线粒体MDC途径的协调 调节质膜和溶酶体养分转运蛋白水平的系统。了解如何 细胞内代谢物触发选择性去除和线粒体营养载体的破坏​​将提供 对轨道内蛋白质分类机制的重要见解，并确定细胞的新模式 代谢调节。