Molecular Regulations of Mitochondrial Structure in Neuronal Homeostasis and Survival

神经元稳态和存活中线粒体结构的分子调控

基本信息

批准号：
10668513
负责人：
XINNAN WANG
金额：
$ 39.35万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668513
关键词：
ATP Synthesis Pathway Address Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Axon Behavior Biochemical Cells Charcot-Marie-Tooth Disease Complex Crista ampullaris Disease Drosophila genus Economics Health Homeostasis Huntington Disease Impairment Inner mitochondrial membrane Knowledge Length Macromolecular Complexes Maintenance Membrane Metabolic Diseases Mission Mitochondria Mitochondrial Crista Mitochondrial Diseases Modification Molecular Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Organism Outcome Oxidative Phosphorylation Oxidative Stress Parkinson Disease Pathogenicity Pathologic Persons Phenotype Phosphorylation Physiological Post-Translational Protein Processing Proliferating Public Health Reaction Regulation Role Series Signal Transduction Site Structure System Testing United States National Institutes of Health crista membrane effective therapy experimental study fly human disease improved in vivo novel therapeutic intervention novel therapeutics oxidation oxidative damage polarized cell response stressor synaptic function

项目摘要

Mitochondrial malfunction is well known to manifest as dysfunction of neurons, due to the high energetic demands of these highly polarized cells, their remarkable axonal length, and complexity. However, how neuronal mitochondria precisely control crista structure in response to ever- changing energy demands and oxidative stressors and how these regulations impact neuronal function and behavior in multicellular organisms remain elusive. In our Preliminary Studies, we have discovered an evolutionarily conserved role for MIC60 in maintaining crista structure in Drosophila. We have found molecular modifications of fly MIC60 (dMIC60) including phosphorylation and oxidation and their significance in maintaining crista junction plasticity and resisting oxidative stress. These results demonstrate the vital importance of dMIC60 and its posttranslational modifications for mitochondrial and neuronal homeostasis. We hypothesize that molecular regulations of dMIC60 including phosphorylation and oxidation allow dMIC60 to receive cellular signals to conduct its functions and that their misregulations could lead to neuronal dysfunction and degeneration. To test this hypothesis, we will perform the following Specific Aims. Aim 1: Roles for dMIC60 in neuronal homeostasis. Aim 2: Crista structure as a cellular cause for oxidative damage. Aim 3: Molecular mechanisms of dMIC60 phosphorylation and oxidation.

线粒体故障众所周知，这表现为神经元的功能障碍，因为高这些高度极化细胞的能量需求，它们的显着轴突长度和复杂性。然而，神经元线粒体如何精确控制Crista结构，以响应不断的不断变化的能量需求和氧化应激源以及这些法规如何影响神经元多细胞生物的功能和行为仍然难以捉摸。在我们的初步研究中，我们已经发现MIC 60在维持Crista结构中的进化作用果蝇。我们发现了蝇米云（DMIC60）的分子修饰磷酸化和氧化及其在维持Crista连接可塑性和抵抗氧化应激。这些结果表明了DMIC60及其ITS的重要性线粒体和神经元稳态的翻译后修饰。我们假设这一点 DMIC60的分子法规，包括磷酸化和氧化，允许DMIC60接收细胞信号进行其功能，并可能导致神经元功能障碍和变性。为了检验这一假设，我们将执行以下特定目标。 AIM 1：DMIC60在神经元体内平衡中的角色。 AIM 2：Crista结构作为蜂窝氧化损伤的原因。 AIM 3：DMIC60磷酸化的分子机制和氧化。