Mitochondrial dysfunction is critical for neurodegeneration in movement disorders. Neurotoxicological models recapitulating movement disorder involve mitochondrial damage including inhibition of mitochondrial complexes. Previously, we demonstrated that neurotoxic models of Parkinson's disease and Manganism showed distinct morphological, electrophysiological and molecular profile indicating disease-specific characteristics. In a recent study, we demonstrated that the transcriptomic changes triggered by the neurotoxic mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA), was significantly different from the profile induced by the neurotoxic mitochondrial complex I inhibitor 1-methyl-4- phenylpyridinium (MPP⁺) and mitochondrial toxin Manganese (Mn). Among the plausible pathways, we surmised that epigenetic mechanisms could contribute to 3-NPA specific transcriptomic profile. To address this, we assessed global and individual lys-specific acetylation profile of Histone H3 and H4 in the 3-NPA neuronal cell model. Our data revealed histone acetylation profile unique to the 3-NPA model that was not noted in the MPP⁺ and Mn models. Among the individual lys, Histone H3K56 showed robust dose and time-dependent hyperacetylation in the 3-NPA model. Chromatin Immunoprecipitation-sequencing (ChIP-seq) revealed that acetylated H3K56 was associated with 13072 chromatin sites, which showed increased occupancy in the transcription start site-promoter site. Acetylated histone H3K56 was associated with 1747 up-regulated and 263 down-regulated genes in the 3-NPA model, which included many up-regulated autophagy and mitophagy genes. Western analysis validated the involvement of PINK1-Parkin dependent mitophagy in the 3-NPA model. We propose that 3-NPA specific chromatin dynamics could contribute to the unique transcriptomic profile with implications for movement disorders.

线粒体功能障碍对于运动障碍中的神经变性至关重要。重述运动障碍的神经毒理学模型涉及线粒体损伤，包括抑制线粒体复合物。以前，我们证明了帕金森病和锰中毒的神经毒性模型显示出不同的形态学、电生理学和分子特征，表明疾病的特异性特征。在最近的一项研究中，我们证明神经毒性线粒体复合物 II 抑制剂 3-硝基丙酸 (3-NPA) 引发的转录组变化与神经毒性线粒体复合物 I 抑制剂 1-甲基-4-苯基吡啶鎓诱导的特征显着不同。 (MPP ⁺) 和线粒体毒素锰 (Mn)。在可能的途径中，我们推测表观遗传机制可能有助于 3-NPA 特定的转录组学特征。为了解决这个问题，我们评估了 3-NPA 神经元细胞模型中组蛋白 H3 和 H4 的全局和个体赖氨酸特异性乙酰化谱。我们的数据揭示了 3-NPA 模型独有的组蛋白乙酰化特征，这在 MPP ⁺和锰模型。在单个赖氨酸中，组蛋白 H3K56 在 3-NPA 模型中表现出强大的剂量和时间依赖性超乙酰化。染色质免疫沉淀测序 (ChIP-seq) 显示乙酰化 H3K56 与 13072 个染色质位点相关，这表明转录起始位点 - 启动子位点的占有率增加。乙酰化组蛋白 H3K56 与 3-NPA 模型中的 1747 个上调基因和 263 个下调基因相关，其中包括许多上调的自噬和线粒体自噬基因。Western 分析验证了 PINK1-Parkin 依赖性线粒体自噬参与 3-NPA 模型。我们建议 3-NPA 特异性染色质动力学可能有助于独特的转录组学特征，并对运动障碍产生影响。