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

项目摘要 脂类是重要的细胞大分子，形成膜，是能量储存的主要形式，发挥作用 在细胞信号转导中起关键作用，在疾病中经常处于失调状态。细胞主要通过两种方式获得脂质： 要么通过从外源吸收，要么通过Fatty在细胞质中合成乙酰辅酶A 酸性合成酶(FASN)。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)。 众所周知，线粒体是“细胞的发动机”。与这一众所周知的功能直接对比的是， 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生物中吸收脂肪 对于细胞的不同区域，人们还不完全了解。事实上，对mtFas的研究如此之少，以至于编码mtFAS的基因 这条道路上的几个步骤仍然没有注释。我的研究小组的主要目标是定义基本的 线粒体Fas途径的生物学研究。 我之前定义了一种机制，mtFAS通过它来协调线粒体的三个主要功能： TCA循环，电子传输链组装，铁-硫团簇生物发生。我们假设这是 线粒体Fas的协调功能为细胞提供了一种监测底物--线粒体乙酰辅酶A的方法 并相应地调节线粒体新陈代谢。调节这种营养素的机制 一般未描述传感功能和mtFas活性。这项提案中计划的研究将解决 在我们对基因和代谢物如何控制mtFas途径活性的理解上存在重大差距。我们还将 探讨mtFas通路作用的细胞类型特异性，以及mtFas在细胞分化信号中的作用 以及细胞命运的决定。确定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和 适应不断变化的营养环境。 由于我在mtas途径功能方面的专业知识和我以前的研究，我非常适合实现这些目标。 在线粒体生物学方面的经验，这是生物能量学、细胞信号和代谢的交叉点 监管。成功完成这些研究将使我和我的实习生走在 线粒体新陈代谢，并为我的实验室长期成功做好准备。

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.