Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation

赖氨酸乙酰化作为视神经萎缩 1 失活的开关

基本信息

批准号：
9887403
负责人：
Ella R Bossy-Wetzel
金额：
$ 51.61万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9887403
关键词：
ATP Synthesis Pathway Acetylation Address Aging Alzheimer&apos s Disease Antibodies Architecture Autosomal Dominant Optic Atrophy Axon Axonal Transport Binding Biological Markers Buffers CRISPR/Cas technology Cell Death Cell Survival Cells Crista ampullaris Cryoelectron Microscopy Data Deacetylase Deacetylation Defect Detection Diagnosis Disease Dominant-Negative Mutation Dynamin Energy Supply Exhibits Family Functional disorder Genetic Code Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Homeostasis Human Hydrolysis In Vitro Injury Inner mitochondrial membrane Knock-out Knowledge Lipid Binding Lysine Maintenance Maps Membrane Membrane Fusion Metabolic Metabolism Microscopy Missense Mutation Mitochondria Mitochondrial DNA Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Optic Atrophy Optic Nerve Organelles Parkinson Disease Pathogenesis Pathogenicity Patients Play Post-Translational Protein Processing Process Proteins Proteomics Research Resolution Respiration Role Site Structural Models Structure Surface Synapses Synaptic Transmission Techniques Testing Time autosomal dominant mutation early onset improved in vivo induced pluripotent stem cell mitochondrial dysfunction mutant neuron loss neuropathology novel novel therapeutic intervention retinal ganglion cell degeneration tomography tool

项目摘要

Neurons depend on mitochondria to supply energy for processes such as synaptic transmission, channel activity, and axonal transport. To meet the constantly changing energy demands of neurons, mitochondria undergo frequent fission and fusion. Fission and fusion enhance respiration, ATP synthesis, Ca2+ homeostasis, clearance of damaged organelles by mitophagy, neuronal function, and cell survival. However, excessive fission and lack of fusion can cause mitochondrial fragmentation and is implicated in neurodegeneration. Mitochondrial fission and fusion are regulated by large GTPases of the dynamin family. Optic Atrophy 1 (OPA1) is required for mitochondrial inner membrane fusion and maintenance of cristae structure, mtDNA, respiration, ATP synthesis, Ca2+ homeostasis, and neuronal cell survival. Significantly, autosomal dominant mutations in OPA1 cause a spectrum of neurodegenerative disorders, including dominant optic atrophy (DOA), characterized by degeneration of retinal ganglion cells (RGCs) and optic nerve axons. The majority of OPA1 missense mutations are located in the conserved GTPase (G) domain and interfere with normal OPA1 function by dominant-negative mechanisms. Thus, inactivation of the G-domain is associated with disease pathogenesis. While OPA1 mutations cause early-onset familial forms of neurodegenerative disease, it is unknown whether OPA1 can also be inactivated in late-onset sporadic diseases. Remarkably, recent high-throughput proteomic screens identified a major lysine acetylation site located in the G-domain and a hotspot of pathogenic OPA1 mutations, predicting a critical functional role. The function of this posttranslational modification (PTM) is unknown. In addition, research tools to investigate the significance of OPA1 lysine acetylation are currently missing. Here, we will investigate whether lysine acetylation in the G-domain is a new PTM regulating OPA1 function. We will address the following questions: (1) Does acetylation inhibit OPA1 GTP hydrolysis? (2) Does acetylated OPA1 inhibit mitochondrial fusion and function? (3) Does OPA1 acetylation play a causal role in neuronal injury and cell death? Lysine acetylation might emerge as a novel mechanism of OPA1 inactivation during aging and contribute to mitochondrial fragmentation and dysfunction in sporadic neurodegenerative disorders. Modulating OPA1 acetylation might be a new neuroprotective strategy.

神经元依赖线粒体为突触传播等过程提供能量活动和轴突运输。为了满足神经元不断变化的能源需求，线粒体经常进行裂变和融合。裂变和融合增强呼吸，ATP合成，Ca2+稳态，通过线粒体，神经元功能和细胞存活对细胞器的清除。但是，过多裂变和缺乏融合会导致线粒体碎片化，并与神经变性有关。线粒体裂变和融合受动力蛋白家族的大GTPase调节。光学萎缩1 （OPA1）是线粒体内膜融合和Cristae结构的维护所必需的，MtDNA，呼吸，ATP合成，Ca2+稳态和神经元细胞存活。值得注意的是，常染色体显性 OPA1中的突变引起神经退行性疾病的频谱，包括显性视神经萎缩（DOA），以视网膜神经节细胞（RGC）和视神经轴突的变性为特征。大多数OPA1 错义突变位于保守的GTPase（G）结构域中，并干扰正常的OPA1功能通过主导的阴性机制。因此，G域的失活与疾病有关发病。虽然OPA1突变会引起早期发作的神经退行性疾病的家族性形式，但尚不清楚在晚期零星疾病中，OPA1是否也可能被灭活。值得注意的是，最近的高通量蛋白质组学筛选确定了位于G域中的主要赖氨酸乙酰化位点和一个热点致病性OPA1突变，预测了关键的功能作用。这种翻译后的功能修改（PTM）未知。此外，研究OPA1赖氨酸意义的研究工具目前缺少乙酰化。在这里，我们将研究G域中的赖氨酸乙酰化是否是调节OPA1的新PTM 功能。我们将解决以下问题：（1）乙酰化是否会抑制OPA1 GTP水解？（2）做乙酰化的OPA1抑制线粒体融合和功能？（3）OPA1乙酰化在神经元损伤和细胞死亡？赖氨酸乙酰化可能会成为OPA1失活的新机制在衰老期间并导致偶发神经退行性的线粒体碎片和功能障碍疾病。调节OPA1乙酰化可能是一种新的神经保护策略。