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Mitochondrial Fatty Acid Synthesis and the Coordinate Regulation of Respiration

线粒体脂肪酸合成与呼吸的协调调节

基本信息

批准号：
10254273
负责人：
Dennis R. Winge
金额：
$ 29.36万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254273
关键词：
Acetyl Coenzyme A Acute Acyl Carrier Protein Acylation Affect Attenuated Binding Biogenesis Biological Models Caprylates Carbon Catabolism Cell Respiration Cell physiology Cells Complex Consumption Coupling Data Disease Enzymes Eukaryotic Cell Exhibits FASN gene Family Fatty Acids Foundations Funding Future Impairment Intervention Iron Lead Mammals Metabolic Mitochondria Mitochondrial Diseases Mutation Nutrient Oxidative Phosphorylation Pathway interactions Physiology Post-Translational Protein Processing Process Protein Family Proteins Proteomics Publishing Regulation Respiration Respiratory System Respiratory physiology Role Scaffolding Protein Sulfur System Testing Therapeutic Thioctic Acid Translating Translations Work Yeasts base cysteine desulfurase fatty acid biosynthesis human disease member mitochondrial genome mitochondrial metabolism novel oligomycin sensitivity-conferring protein respiration regulation respiratory response scaffold

项目摘要

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.

项目概要拟议的项目是先前资助项目的更新，该项目的重点是线粒体呼吸组装因子的发现和表征复合物。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。当这条路是活性，它合成共价连接到 Acp1 支架的酰基链蛋白质，当酰化时结合并激活 LYR 调节因子家族呼吸复合物组装和铁硫簇生物发生所需的。我们进一步证明 mtFAS 的活性和 Acp1 的酰化状态对线粒体乙酰辅酶A的可用性，这也是主要的燃料线粒体氧化代谢。因此，我们假设该系统提供一种优雅的机制，可以耦合组装和激活线粒体呼吸系统及其可用的底物。到检验这个假设并更好地定义潜在机制，我们提出以下建议目标。目标1）明确mtFAS在铁硫簇调控中的作用合成。目标 2) 定义 OXPHOS 的 mtFAS 和 LYR 依赖性调节生物发生。目标 3) 发现并表征 mtFAS 和 ACP 的新靶点规定。我们建议更好地了解 mtFAS 及其调节方式 Acp1 靶标的激活可能会带来增强和优化的治疗方法线粒体呼吸。