Mitochondrial Fatty Acid Synthesis and the Coordinate Regulation of Respiration

项目摘要 拟议的项目是对以前资助的项目的更新，该项目的重点是 线粒体呼吸系统组装因子的发现与鉴定 复合体。在这些研究中，我们意外地观察到 这些络合物的组装和激活严格依赖于相当差的 了解线粒体脂肪酸合成(MtFas)途径。当这条路径是 活性，它合成共价连接到Acp1支架上的酰基链 蛋白质，当被酰化时，它结合并激活LYR家族的调节因子，这些调节因子 呼吸复合体组装和铁-硫簇生物发生所需的。我们进一步 表明线粒体Fas的活性和Acp1的酰化状态对 线粒体乙酰-辅酶A的可用性，这也是 线粒体氧化代谢。因此，我们假设这个系统提供了 一种优雅的机制，使组装和激活 线粒体呼吸系统与该系统的底物的可用性。至 验证这一假设并更好地定义潜在机制，我们提出以下建议 目标。目的1)确定mtFas在铁-硫簇调控中的作用 综合。目的2)确定OXPHOS的mtFas和LYR依赖的调控 生物发生学。目的3)发现和鉴定mtFas和ACP的新靶点 监管。我们建议，更好地理解mtFAS及其如何监管 激活Acp1靶点可能导致促进和优化治疗方法 线粒体呼吸作用。

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.