Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India.
Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India.
Life Sci. 2022 Feb 1;290:120226. doi: 10.1016/j.lfs.2021.120226. Epub 2021 Dec 23.
The multi-factorial Parkinson's disease (PD) is known to be associated with mitochondrial dysfunction, endoplasmic reticulum stress, alpha synuclein aggregation and dopaminergic neuronal death, with oxidative stress being a common denominator to these underlying processes. The perception of mitochondria being 'just ATP producing compartments' have been counterpoised as studies, particularly related to PD, have underlined their strong role in cause and progression of the disease. During PD pathogenesis, neurons encounter chronic stress conditions mainly due to failure of Mitochondrial Quality Control (MQC) machinery. To dissect the regulatory understanding of mitochondrial dysfunction during neurological disease progression, we endeavored to identify key regulatory endpoints that control multiple facets of MQC machinery. Our studies, employing transgenic C. elegans strain expressing human α-synuclein, led us to identification of mitochondrial genes nuo-5 (involved in oxidative phosphorylation), F25B4.7 (exhibits ATP transmembrane transporter activity) and C05D11.9 (having ribonuclease activity), which form predicted downstream targets of most elevated and down-regulated mi-RNA molecules. RNAi mediated silencing, gene ontology and functional genomics analysis studies demonstrated their role in modulating major MQC pathways. The attenuated MQC pathways mainly affected clearance of misfolded and aggregated proteins, redox homeostasis and longevity with compromised dopaminergic functions. Overexpression of the mitochondrial genes by 3 beta-hydroxyl steroid, Tomatidine, was found to curtail the redox imbalance thus leading to amelioration of effects associated with PD and an increase in the lifespan of treated nematodes. Therefore, this study unveils the regulatory role of mitochondrial genes as critical modulators of stress control involved in effects associated with PD pathogenesis.
多因素帕金森病（PD）已知与线粒体功能障碍、内质网应激、α-突触核蛋白聚集和多巴胺能神经元死亡有关，氧化应激是这些潜在过程的共同因素。人们对线粒体“仅仅是产生 ATP 的隔室”的看法已经被推翻，因为特别是与 PD 相关的研究强调了它们在疾病的原因和进展中的重要作用。在 PD 发病机制中，神经元主要由于线粒体质量控制（MQC）机制的失效而遇到慢性应激条件。为了剖析线粒体功能障碍在神经疾病进展过程中的调控机制，我们努力确定控制 MQC 机制多个方面的关键调控终点。我们的研究采用表达人α-突触核蛋白的转基因秀丽隐杆线虫品系，发现了线粒体基因 nuo-5（参与氧化磷酸化）、F25B4.7（表现出 ATP 跨膜转运活性）和 C05D11.9（具有核糖核酸酶活性），它们是大多数上调和下调的 miRNA 分子的预测下游靶点。RNAi 介导的沉默、基因本体和功能基因组学分析研究表明，它们在调节主要的 MQC 途径中发挥作用。衰减的 MQC 途径主要影响错误折叠和聚集蛋白的清除、氧化还原稳态和长寿，以及多巴胺能功能受损。3β-羟基类固醇番茄啶的过表达被发现可以减弱氧化还原失衡，从而改善与 PD 相关的影响，并增加治疗线虫的寿命。因此，这项研究揭示了线粒体基因作为与 PD 发病机制相关的应激控制关键调节剂的调控作用。
