Melatonin biosynthesis in neuronal mitochondria

褪黑素是一种具有多效性的神经保护激素，其中许多受 线粒体。褪黑素存在于神经元线粒体中。然而，人们对这种合成或 褪黑素在神经元中的运输。我们的初步数据表明褪黑素是在神经元中产生的。 线粒体，这个项目的假设是神经元褪黑素是在线粒体中合成的 线粒体中的AANAT活性(褪黑素合成途径中的限速酶)是 受磷酸化和与14-3-3伴侣相互作用的调节，以及在细胞内合成的褪黑素 线粒体保留在神经元中，在那里它在局部作用，以保护神经元免受细胞压力的影响。为了测试这一点 假设，我们将提出一个研究设计，以实现三个目标。目标1将描述 线粒体褪黑素合成途径，包括四种褪黑素合成酶的定位 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 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 线粒体产生的褪黑素的运输。该项目产生的数据将提供一种新颖的 为了解褪黑素对神经元的保护作用奠定基础并开辟新的研究途径 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.