Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation

神经元依靠线粒体为突触传递、通道等过程提供能量 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 经历频繁的裂变和融合。裂变和融合增强了呼吸作用、ATP合成、钙离子稳态， 通过吞噬有丝分裂、神经元功能和细胞存活清除受损细胞器。然而，过度 分裂和缺乏融合可导致线粒体碎裂，并与神经退行性变有关。 线粒体的分裂和融合是由动力蛋白家族的大GTP酶调控的。视神经萎缩1 (OPA1)是线粒体内膜融合和维持线粒体脊结构、mtDNA、 呼吸、三磷酸腺苷合成、钙离子稳态和神经细胞存活。值得注意的是，常染色体显性 OPA1基因突变导致一系列神经退行性疾病，包括显性视神经萎缩(DOA)， 以视网膜神经节细胞(RGC)和视神经轴突变性为特征。OPA1的大部分 错义突变位于保守的GTPase(G)结构域，干扰正常的OPA1功能 通过显性-负性机制。因此，G结构域的失活与疾病有关 发病机制。 虽然OPA1突变会导致早发性家族性神经退行性疾病，但目前尚不清楚 OPA1在晚发型散发性疾病中是否也可以失活。值得注意的是，最近的高吞吐量 蛋白质组学筛选确定了位于G结构域的一个主要赖氨酸乙酰化位点和一个热点 致病的OPA1突变，预测了一个关键的功能作用。这个翻译后的功能 修改(PTM)未知。此外，研究工具调查OPA1赖氨酸的意义 乙酰化是目前缺失的。 在这里，我们将研究G结构域中的赖氨酸乙酰化是否是一种新的调节OPA1的PTM 功能。我们将解决以下问题：(1)乙酰化是否抑制OPA1 GTP的水解？(2)是否 乙酰化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？赖氨酸乙酰化可能成为OPA1失活的一种新机制 在衰老过程中导致散发性神经退行性变的线粒体碎裂和功能障碍 精神错乱。调节OPA1乙酰化可能是一种新的神经保护策略。

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.