Mitochondrial Fatty Acid Synthesis and the Coordinate Regulation of Respiration

项目摘要 拟议的项目是以前资助的项目的延续，该项目的重点是 线粒体呼吸系统组装因子的发现和鉴定 配合物在这些研究中，我们意外地观察到， 这些复合物的组装和活化严格依赖于 线粒体脂肪酸合成（mtFAS）途径。当这条路 活性，它合成共价连接到Acp 1支架的酰基链 蛋白质，当酰化时结合并激活LYR家族的调节因子， 呼吸复合体组装和铁硫簇生物发生所需的。我们进一步 证明了mtFAS的活性和Acp 1的酰化状态对 线粒体乙酰辅酶A的可用性，这也是主要的燃料 线粒体氧化代谢因此，我们假设该系统提供了 一个优雅的机制，使耦合的组装和激活的 线粒体呼吸系统与该系统的底物的可用性。到 为了检验这一假设并更好地定义潜在的机制，我们提出以下建议 目标。目的1）明确线粒体FAS在铁硫簇调控中的作用 合成.目的2）定义OXPHOS的mtFAS和LYR依赖性调节 生物起源目的3）发现和表征mtFAS和ACP的新靶点 调控我们建议，更好地了解mtFAS及其如何调节 激活Acp1靶点可能会导致治疗方法， 线粒体呼吸

Project Summary The proposed project is a renewal of a previously funded project that was focused on the discovery and characterization of assembly factors for the mitochondrial respiratory complexes. During these studies, we made the unexpected observation that the assembly and activation of those complexes is strictly dependent upon the rather poorly understood mitochondrial fatty acid synthesis (mtFAS) pathway. When this pathway is active, it synthesizes acyl chains that are covalently attached to the Acp1 scaffold protein, which when acylated binds and activates the LYR family of regulators that are required for respiratory complex assembly and iron-sulfur cluster biogenesis. We further demonstrated that the activity of mtFAS and the acylation state of Acp1 is sensitive to the availability of mitochondrial acetyl-coA, which is also the principal fuel for mitochondrial oxidative metabolism. Therefore, we hypothesize that this system provides an elegant mechanism to enable the coupling of assembly and activation of the mitochondrial respiratory system with the availability of substrates for that system. To test this hypothesis and better define the underlying mechanisms, we propose the follow aims. Aim 1) Define the role of mtFAS in the regulation of iron-sulfur cluster synthesis. Aim 2) Define the mtFAS and LYR-dependent regulation of OXPHOS biogenesis. Aim 3) Discover and characterize novel targets of mtFAS and ACP regulation. We propose that a better understanding of mtFAS and how it regulates activation of Acp1 targets could lead to therapeutic approaches to boost and optimize mitochondrial respiration.