Melatonin biosynthesis in neuronal mitochondria

褪黑激素是一种具有多效性的神经保护激素，其中许多是由 线粒体褪黑素存在于神经元线粒体中。然而，对合成或 褪黑激素在神经元中的转运。我们的初步数据表明，褪黑激素是在神经元中产生的。 该项目的假设是，神经元褪黑激素是在线粒体中合成的。 线粒体中AANAT活性（褪黑激素合成途径中的限速酶）被 通过磷酸化和与14-3-3分子伴侣的相互作用来调节， 线粒体保留在神经元中，在那里它局部地起作用以保护神经元免受细胞应激。为了验证这一 假设，我们将提出一个研究设计，将实现三个目标。目标1将描述 线粒体褪黑激素合成途径，包括定位四种褪黑激素合成酶 并确定它们如何被运输到亚细胞膜和细胞器。在目标2中，我们将确定 负责调节神经元中褪黑激素合成的机制。目标3将重点放在细胞内 大脑产生的褪黑激素的运输。从这个项目产生的数据将提供一个新的 为了解褪黑激素对神经元的保护作用奠定了基础，并开辟了一条新的研究途径 用于线粒体褪黑激素药理学和生物学。

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.