Odnokoz Olena, Nakatsuka Kyle, Wright Corbin, Castellanos Jovelyn, Klichko Vladimir I, Kretzschmar Doris, Orr William C, Radyuk Svetlana N
Department of Biological Sciences, Southern Methodist University, Dallas, TX, United States.
Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, OR, United States.
Front Cell Dev Biol. 2021 Jan 28;9:613036. doi: 10.3389/fcell.2021.613036. eCollection 2021.
Mitochondrial dysfunction often leads to neurodegeneration and is considered one of the main causes of neurological disorders, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other age-related diseases. Mitochondrial dysfunction is tightly linked to oxidative stress and accumulating evidence suggests the association between oxidative stress and neurological disorders. However, there is insufficient knowledge about the role of pro-oxidative shift in cellular redox and impairment of redox-sensitive signaling in the development of neurodegenerative pathological conditions. To gain a more complete understanding of the relationship between mitochondria, redox status, and neurodegenerative disorders, we investigated the effect of mitochondrial thiol-dependent peroxidases, peroxiredoxins (Prxs), on the physiological characteristics of flies, which change with pathologies such as PD, ALS and during aging. We previously found that through their ability to sense changes in redox and regulate redox-sensitive signaling, Prxs play a critical role in maintaining global thiol homeostasis, preventing age-related apoptosis and chronic activation of the immune response. We also found that the phenotype of flies under-expressing Prxs in mitochondria shares many characteristics with the phenotype of models of neurological disorders such as ALS, including impaired locomotor activity and compromised redox balance. Here, we expanded the study and found that under-expression of mitochondrial Prxs leads to behavioral changes associated with neural function, including locomotor ability, sleep-wake behavior, and temperature-sensitive paralysis. We also found that under-expression of mitochondrial Prxs with a motor-neuron-specific driver, D42-GAL4, was a determining factor in the development of the phenotype of shortened lifespan and impaired motor activity in flies. The results of the study suggest a causal link between mitochondrial Prx activity and the development of neurological disorders and pre-mature aging.
线粒体功能障碍常导致神经退行性变，被认为是神经疾病（如帕金森病（PD）、肌萎缩侧索硬化症（ALS）和其他与年龄相关的疾病）的主要病因之一。线粒体功能障碍与氧化应激紧密相关，越来越多的证据表明氧化应激与神经疾病之间存在关联。然而，关于细胞氧化还原过程中促氧化转变的作用以及氧化还原敏感信号受损在神经退行性病理状况发展中的作用，我们了解得还不够充分。为了更全面地理解线粒体、氧化还原状态和神经退行性疾病之间的关系，我们研究了线粒体硫醇依赖性过氧化物酶——过氧化物氧还蛋白（Prxs）对果蝇生理特征的影响，这些生理特征会随着PD、ALS等病理状况以及衰老过程而发生变化。我们之前发现，Prxs通过其感知氧化还原变化和调节氧化还原敏感信号的能力，在维持整体硫醇稳态、预防与年龄相关的细胞凋亡以及免疫反应的慢性激活方面发挥着关键作用。我们还发现，线粒体中Prxs表达不足的果蝇的表型与ALS等神经疾病模型的表型有许多共同特征，包括运动能力受损和氧化还原平衡受损。在此，我们扩展了这项研究，发现线粒体Prxs的表达不足会导致与神经功能相关的行为变化，包括运动能力、睡眠 - 觉醒行为和温度敏感性麻痹。我们还发现，使用运动神经元特异性驱动子D42 - GAL4使线粒体Prxs表达不足，是果蝇寿命缩短和运动活动受损表型发展的一个决定性因素。该研究结果表明线粒体Prx活性与神经疾病的发展以及早衰之间存在因果联系。
