DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
复制标题
DOI：
10.1016/j.nbd.2022.105941
复制
发表时间：
2023-01-01
影响因子：
6.1
通讯作者：
Bisaglia, Marco
中科院分区：
文献类型：
--
作者：
De Lazzari, Federica;Agostini, Francesco;Bisaglia, Marco
在罕见的家族性隐性帕金森病和伴有肌萎缩侧索硬化症状和痴呆的帕金森病中，DJ-1蛋白发生突变。DJ-1被认为是一种多任务蛋白，能够在各种压力条件下提供保护。然而，精确的细胞功能仍然难以捉摸。在目前的工作中，我们评估了缺乏DJ-1同源物DJ-1 β表达的果蝇，与对照年龄匹配的个体相比。行为评估包括寿命、在露天竞技场的运动、对氧化损伤的敏感性和对饥饿的抵抗力。通过分析线粒体形态、功能和自噬反应进行分子分析。我们证明了j-1 β零突变果蝇活性低下，对氧化损伤和食物剥夺表现出更高的敏感性。线粒体稳态分析显示，dj-1 β的缺失导致线粒体更大、更圆，其特征是复合物i连接呼吸受损，同时保持ATP的生产能力。此外，dj-1 β零突变果蝇表现出受损的自噬反应，这被抗氧化剂分子n -乙酰- l-半胱氨酸抑制。总的来说，我们的数据指出了一种机制，即DJ-1通过维持线粒体稳态和通过维持细胞氧化还原状态影响自噬通量，在维持能量稳态中发挥关键作用。鉴于DJ-1参与神经退行性疾病，并考虑到神经元是高能量需求细胞，对氧化还原应激特别敏感，我们的研究揭示了DJ-1在维持细胞稳态中的关键作用。
The protein DJ-1 is mutated in rare familial forms of recessive Parkinson's disease and in parkinsonism accompanied by amyotrophic lateral sclerosis symptoms and dementia. DJ-1 is considered a multitasking protein able to confer protection under various conditions of stress. However, the precise cellular function still remains elusive. In the present work, we evaluated fruit flies lacking the expression of the DJ-1 homolog dj-1beta as compared to control aged-matched individuals. Behavioral evaluations included lifespan, locomotion in an open field arena, sensitivity to oxidative insults, and resistance to starvation. Molecular analyses were carried out by analyzing the mitochondrial morphology and functionality, and the autophagic response. We demonstrated that dj-1beta null mutant flies are hypoactive and display higher sensitivity to oxidative insults and food deprivation. Analysis of mitochondrial homeostasis revealed that loss of dj-1beta leads to larger and more circular mitochondria, characterized by impaired complex-I-linked respiration while preserving ATP production capacity. Additionally, dj-1beta null mutant flies present an impaired autophagic response, which is suppressed by treatment with the antioxidant molecule N-Acetyl-L-Cysteine. Overall, our data point to a mechanism whereby DJ-1 plays a critical role in the maintenance of energy homeostasis, by sustaining mitochondrial homeostasis and affecting the autophagic flux through the maintenance of the cellular redox state. In light of the involvement of DJ-1 in neurodegenerative diseases and considering that neurons are highly energy-demanding cells, particularly sensitive to redox stress, our study sheds light on a key role of DJ-1 in the maintenance of cellular homeostasis.