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

• 批准号: 10558741
• 负责人: Blaise Bossy
• 金额: $ 40.04万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-05-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558741
• 关键词: ATP Synthesis Pathway; Acetylation; Aging; Alzheimer' 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; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Optic Atrophy; Optic Nerve; Optic atrophy 1; Organelles; Parkinson Disease; Pathogenesis; Pathogenicity; Patients; Play; Post-Translational Protein Processing; Process; Proteins; Proteomics; Research; Resolution; Respiration; Role; Site; Structure; Surface; Synapses; Synaptic Transmission; Techniques; Testing; autosomal dominant mutation; early onset; improved; in vivo; induced pluripotent stem cell; mitochondrial dysfunction; mutant; neuron loss; neuropathology; neuroprotection; novel; novel therapeutic intervention; optical switch; retinal ganglion cell degeneration; tomography; tool; ultra high resolution

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递、通道传递等过程提供能量。 活动和轴突运输。为了满足神经元不断变化的能量需求，线粒体 经历频繁的裂变和聚变。分裂和融合增强呼吸、ATP合成、Ca 2+稳态， 通过线粒体自噬清除受损的细胞器、神经元功能和细胞存活。但过度 分裂和融合的缺乏可导致线粒体断裂并与神经变性有关。 线粒体分裂和融合受发动蛋白家族的大GTP酶调节。视神经萎缩1 OPA 1是线粒体内膜融合和嵴结构，mtDNA， 呼吸、ATP合成、Ca 2+稳态和神经元细胞存活。常染色体显性遗传 OPA 1的突变引起一系列神经变性疾病，包括显性视神经萎缩（DOA）， 其特征在于视网膜神经节细胞（RGC）和视神经轴突的变性。大多数OPA 1 错义突变位于保守的GT3（G）结构域，干扰正常的OPA 1功能 负显性机制。因此，G-结构域的失活与疾病相关， 发病机制 虽然OPA 1突变导致早发性家族性神经退行性疾病，但尚不清楚 OPA 1是否也可以在迟发性散发性疾病中失活。值得注意的是，最近的高通量 蛋白质组学筛选确定了一个主要的赖氨酸乙酰化位点位于G-结构域和一个热点， 致病性OPA 1突变，预测关键的功能作用。这种翻译后的功能 修改（PTM）未知。此外，研究工具，以调查的意义，OPA 1赖氨酸 目前缺少乙酰化。 在这里，我们将调查是否赖氨酸乙酰化的G-域是一个新的PTM调节OPA 1 功能我们将解决以下问题：（1）乙酰化是否抑制OPA 1 GTP水解？(2)并 乙酰化OPA 1抑制线粒体融合和功能？(3)OPA 1乙酰化是否在 神经元损伤和细胞死亡赖氨酸乙酰化可能是OPA 1失活的一种新机制 衰老期间并导致散发性神经退行性疾病中的线粒体断裂和功能障碍 紊乱调节OPA 1乙酰化可能是一种新的神经保护策略。