Melatonin biosynthesis in neuronal mitochondria

神经元线粒体中褪黑激素的生物合成

• 批准号: 9444739
• 负责人: Robert M. Friedlander
• 金额: $ 39.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444739
• 关键词: Acetyltransferase; Anabolism; Arylalkylamine N-Acetyltransferase; Binding; Biology; Caspase; Cell Nucleus; Cell membrane; Cellular Stress; Circadian Rhythms; Computer Simulation; Cytosol; Data; Environment; Enzymes; Feedback; Foundations; Free Radical Scavengers; Free Radicals; Functional disorder; G-Protein-Coupled Receptors; Generations; Genes; Hormones; Intracellular Transport; Melatonin; Melatonin Receptors; Membrane; Messenger RNA; Methyltransferase; Mitochondria; Mitochondrial Matrix; Molecular Chaperones; Neurons; Neuroprotective Agents; Organelles; Pathway interactions; Pharmacology; Phosphorylation; Pineal gland; Post-Translational Protein Processing; Process; Property; Protein Import; Proteins; Regulation; Research; Research Design; Respiration; Respiratory Chain; Role; Signal Transduction; Source; Subcellular Fractions; System; Testing; brain health; cofactor; cytochrome c; enzyme pathway; experimental study; innovation; neuronal survival; novel

Melatonin is a neuroprotective hormone with pleiotropic properties, many of which are modulated by the mitochondria. Melatonin is found in neuronal mitochondria. However, little is known about the synthesis or transport of melatonin in neurons. Our preliminary data suggest that melatonin is produced in neuronal mitochondria and the hypothesis of this project is that neuronal melatonin is synthesized in the mitochondrial matrix; that AANAT activity (the rate limiting enzyme in the melatonin synthesis pathway) in the mitochondria is regulated by phosphorylation and interaction with the 14-3-3 chaperone, and that melatonin synthesized in the mitochondria remains in the neuron where it acts locally to protect neurons from cellular stress. To test this hypothesis, we will propose a research design that will accomplish three Aims. Aim 1 will characterize the mitochondrial melatonin synthesis pathway, including localizing each of the four melatonin synthesis enzymes and determining how they are transported to subcellular membrane and organelles. In Aim 2 we will determine the mechanisms responsible for regulating melatonin synthesis in neurons. Aim 3 will focus on the intracellular transport of mitochondrially-produced melatonin. The data generated from this project will provide a novel foundation for understanding the protective action of melatonin on neurons and opens a new research avenue for mitochondrial melatonin pharmacology and biology.

褪黑激素是一种具有多效特性的神经保护激素，其中许多是由 线粒体。褪黑激素在神经元线粒体中发现。但是，关于合成或 神经元中褪黑激素的运输。我们的初步数据表明褪黑激素是在神经元中产生的 线粒体和该项目的假设是神经元褪黑激素是在线粒体中合成的 矩阵;线粒体中的AANAT活性（褪黑激素合成途径中的速率限制酶）为 由磷酸化和与14-3-3伴侣的相互作用调节，并在 线粒体保留在神经元中，该神经元在局部作用可保护神经元免受细胞应激。测试这个 假设，我们将提出一种研究设计，该设计将实现三个目标。 AIM 1将表征 线粒体褪黑激素合成途径，包括定位四种褪黑激素合成酶 并确定它们是如何运输到亚细胞膜和细胞器的。在AIM 2中，我们将确定 负责调节神经元中褪黑激素合成的机制。 AIM 3将重点放在细胞内 线粒体生产的褪黑激素的运输。该项目产生的数据将提供小说 理解褪黑激素对神经元的保护作用的基础，并打开了新的研究途径 线粒体褪黑激素药理学和生物学。