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.

项目摘要拟议的项目是对以前资助的项目的续签，该项目的重点是线粒体呼吸系统组装因子的发现和表征复合物。在这些研究中，我们表达了意外的观察这些复合物的组装和激活严格取决于相当差的理解的线粒体脂肪酸合成（MTFAS）途径。当这条路是活跃，它合成了共同附着在ACP1支架上的酰基链蛋白质，当酰化结合并激活lyr的调节剂家族时呼吸复合物组装和铁硫簇生物发生所需。我们进一步证明MTFA的活性和ACP1的酰化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，我们假设该系统提供一种优雅的机制，可以使组装耦合和激活线粒体呼吸系统具有该系统的底物的可用性。到检验该假设并更好地定义潜在机制，我们提出以下目标。目标1）定义mTFA在铁硫簇调节中的作用合成。目标2）定义oxphos的mtfas和lyl依赖性调节生物发生。目标3）发现并表征了MTFA和ACP的新目标规定。我们建议对MTFA及其调节方式有更好的了解 ACP1靶标的激活可能导致治疗方法来提高和优化线粒体呼吸。