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

项目摘要 脂质是形成膜的重要细胞大分子，是能量储存的主要形式， 在细胞信号传导中起着至关重要的作用，并且在疾病中经常失调。细胞通过两种主要方式获得脂质： 或者通过从外源来源摄取，或者通过脂肪酶在细胞质中从乙酰辅酶A合成， 酸性合成酶（Festival）。然而，细胞在进化过程中保持了第二种完全不同的脂肪酸， 线粒体合成途径（mtFAS）。 线粒体被称为“细胞的发电站”。与这个众所周知的功能直接相反， 线粒体FAS途径使用乙酰辅酶A来构建脂肪酸，而不是将其分解。为什么是线粒体 拥有一条构建脂肪酸的途径，特别是考虑到线粒体从其他细胞中摄取脂质， 细胞的区域还不完全清楚。事实上，mtFAS的研究是如此不足， 路径中的几个步骤仍然没有注释。我的研究小组的主要目标是确定 mtFAS途径的生物学。 我以前定义了一种机制，通过这种机制，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成因。我们假设这 线粒体FAS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， 并相应地调整线粒体代谢。调节这种营养物质的机制 一般而言，未描述传感功能和mtFAS活性。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线粒体FAS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 代谢物的可用性将改写该领域关于线粒体如何感知营养物质的工作模型， 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我之前的研究，我非常适合实现这些目标 在线粒体生物学的经验，这是在生物能量学，细胞信号和代谢的交叉点 调控成功完成这些研究将使我和我的学员在该领域的最前沿， 线粒体代谢，并为我的实验室的长期成功做好准备。

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.