Regulation of mitochondrial fatty acid synthesis in the control of mitochondrial metabolism.

线粒体脂肪酸合成的调节在线粒体代谢的控制中。

• 批准号: 10714923
• 负责人: Sara Marie Nowinski
• 金额: $ 47.5万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714923
• 关键词: Acetyl Coenzyme A; Area; Bioenergetics; Biogenesis; Biology; Cells; Citric Acid Cycle; Cultured Cells; Cytoplasm; Data; Disease; Disparate; Electron Transport; Environment; Fatty Acids; Fatty-acid synthase; Genes; Goals; Iron; Laboratories; Lipids; Mammals; Membrane; Metabolic; Metabolism; Mitochondria; Modeling; Monitor; Nutrient availability; Nutritional; Pathway interactions; Play; Positioning Attribute; Regulation; Research; Role; Signal Transduction; Source; Specificity; Sulfur; Supporting Cell; System; Tissues; Writing; Yeasts; cell type; detection of nutrient; experience; experimental study; macromolecule; mitochondrial metabolism; response; success; uptake

Project Summary Lipids are important cellular macromolecules that form membranes, are a major form of energy storage, play crucial roles in cell signaling, and are frequently dysregulated in disease. Cells obtain lipids in two main ways: either through uptake from exogenous sources or else via synthesis from acetyl-CoA in the cytoplasm by Fatty Acid Synthase (FASN). However, cells have evolutionarily maintained a second, completely distinct fatty acid synthesis pathway in the mitochondria (mtFAS). Mitochondria are well known as the “powerhouse of the cell.” In direct contrast to this well-known function, the mtFAS pathway uses acetyl-CoA to build fatty acids instead of breaking them down. Why mitochondria harbor a pathway that builds fatty acids, especially given that mitochondria take up lipids from other areas of the cell, is incompletely understood. In fact, mtFAS is so understudied that the genes encoding several steps in the pathway are still unannotated. The major goal of my research group is to define the basic biology of the mtFAS pathway. I previously defined a mechanism whereby mtFAS coordinates three major functions of the mitochondria: the TCA cycle, electron transport chain assembly, and iron-sulfur cluster biogenesis. We hypothesize that this coordinating function of mtFAS provides cells with a means to monitor mitochondrial acetyl-CoA – the substrate of the pathway – and to adjust mitochondrial metabolism accordingly. The mechanisms that regulate this nutrient sensing function and mtFAS activity in general are undescribed. The studies planned in this proposal will address crucial gaps in our understanding of how genes and metabolites control mtFAS pathway activity. We will also explore cell-type specificity of mtFAS pathway action, and the role of mtFAS in cellular differentiation signaling and cell fate decisions. Defining how mtFAS regulates mitochondrial function in response to changes in metabolite availability will rewrite the field’s working model of how mitochondria sense nutrients and adapt to changing nutritional environments. I am well suited to achieve these goals due to my expertise in mtFAS pathway function and my prior research experience in mitochondrial biology, which lies at the intersection of bioenergetics, cell signaling, and metabolic regulation. Successful completion of these studies will place me and my trainees at the forefront of the field of mitochondrial metabolism, and well-position my laboratory for long-term success.

项目概要 脂质是形成细胞膜的重要细胞大分子，是能量储存、发挥作用的主要形式 在细胞信号传导中发挥着至关重要的作用，并且在疾病中经常失调。细胞通过两种主要方式获得脂质： 要么通过外源摄取，要么通过 Fatty 从细胞质中的乙酰辅酶 A 合成 酸合酶（FASN）。然而，细胞在进化过程中保留了第二种完全不同的脂肪酸 线粒体合成途径（mtFAS）。 线粒体被誉为“细胞的发电站”。与这个众所周知的函数形成鲜明对比的是， mtFAS 途径使用乙酰辅酶 A 来构建脂肪酸而不是分解它们。为什么选择线粒体 拥有一条构建脂肪酸的途径，特别是考虑到线粒体从其他物质中吸收脂质 细胞的各个区域，目前尚不完全清楚。事实上，mtFAS 的研究还很不够，编码基因 该路径中的几个步骤仍未注释。我的研究小组的主要目标是定义基本的 mtFAS 途径的生物学。 我之前定义了一种机制，通过 mtFAS 协调线粒体的三个主要功能： TCA 循环、电子传递链组装和铁硫簇生物发生。我们假设这 mtFAS 的协调功能为细胞提供了一种监测线粒体乙酰辅酶 A（底物）的方法 途径的影响——并相应地调整线粒体代谢。调节这种营养素的机制 传感功能和 mtFAS 活性一般未描述。本提案中计划的研究将解决 我们对基因和代谢物如何控制 mtFAS 通路活性的理解存在重大差距。我们还将 探索 mtFAS 通路作用的细胞类型特异性，以及 mtFAS 在细胞分化信号传导中的作用 和细胞命运的决定。定义 mtFAS 如何调节线粒体功能以响应线粒体的变化 代谢物的可用性将改写该领域线粒体如何感知营养物质和 适应不断变化的营养环境。 由于我在 mtFAS 通路功能方面的专业知识和之前的研究，我非常适合实现这些目标 线粒体生物学经验，涉及生物能量学、细胞信号传导和代谢的交叉点 规定。成功完成这些研究将使我和我的学员处于该领域的最前沿 线粒体代谢，并为我的实验室取得长期成功做好准备。