Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster.
Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster.
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DOI：
10.1371/journal.pone.0050454
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Giebultowicz JM
中科院分区：
文献类型：
--
作者：
Beaver LM;Klichko VI;Chow ES;Kotwica-Rolinska J;Williamson M;Orr WC;Radyuk SN;Giebultowicz JM
昼夜节律钟产生神经元、生理和代谢功能的日常节律。先前对哺乳动物的研究报告了主要内源性抗氧化剂谷胱甘肽（GSH）水平的每日波动，但控制这种波动的分子机制尚不清楚。为了解决这个问题，我们使用了具有丰富遗传工具库的模式物种果蝇。在此之前，我们发现生物钟的缺失会增加大脑的氧化损伤并导致神经退行性变化，而神经元组织中GSH的产生增加对正常和应激条件下果蝇的存活有有益的影响。在目前的研究中，我们报告了蝇头中谷胱甘肽的浓度以生物钟依赖的方式波动。我们进一步证明了谷氨酸半胱氨酸连接酶（GCL）活性的节律，GCL是谷胱甘肽生物合成的限速酶。编码催化（Gclc）和调节（Gclm）亚基（包括GCL全酶）的基因mRNA水平也有显著的节律。此外，我们发现谷胱甘肽s -转移酶GstD1的表达在昼夜节律中显著波动，GstD1利用谷胱甘肽进行细胞解毒。为了直接解决时钟在调节GSH相关节律中的作用，我们在时钟基因周期和周期零突变的果蝇中评估了GCL亚基和GstD1的表达水平，以及GCL活性和GSH产生。在对照蝇中观察到的节律在生物钟突变体中并不明显，因此将谷胱甘肽的产生和利用与昼夜节律系统联系起来。总之，这些数据表明，昼夜节律系统调节参与生产和谷胱甘肽利用的途径。
Circadian clocks generate daily rhythms in neuronal, physiological, and metabolic functions. Previous studies in mammals reported daily fluctuations in levels of the major endogenous antioxidant, glutathione (GSH), but the molecular mechanisms that govern such fluctuations remained unknown. To address this question, we used the model species Drosophila, which has a rich arsenal of genetic tools. Previously, we showed that loss of the circadian clock increased oxidative damage and caused neurodegenerative changes in the brain, while enhanced GSH production in neuronal tissue conferred beneficial effects on fly survivorship under normal and stress conditions. In the current study we report that the GSH concentrations in fly heads fluctuate in a circadian clock-dependent manner. We further demonstrate a rhythm in activity of glutamate cysteine ligase (GCL), the rate-limiting enzyme in glutathione biosynthesis. Significant rhythms were also observed for mRNA levels of genes encoding the catalytic (Gclc) and modulatory (Gclm) subunits comprising the GCL holoenzyme. Furthermore, we found that the expression of a glutathione S-transferase, GstD1, which utilizes GSH in cellular detoxification, significantly fluctuated during the circadian day. To directly address the role of the clock in regulating GSH-related rhythms, the expression levels of the GCL subunits and GstD1, as well as GCL activity and GSH production were evaluated in flies with a null mutation in the clock genes cycle and period. The rhythms observed in control flies were not evident in the clock mutants, thus linking glutathione production and utilization to the circadian system. Together, these data suggest that the circadian system modulates pathways involved in production and utilization of glutathione.
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DOI：
10.1073/pnas.1118726109
发表时间：
2012-04-03
影响因子：
11.1
作者：
Eckel-Mahan, Kristin L.;Patel, Vishal R.;Sassone-Corsi, Paolo
通讯作者：
Sassone-Corsi, Paolo
影响因子：
10.6
作者：
Forman, Henry Jay;Zhang, Hongqiao;Rinna, Alessandra
通讯作者：
Rinna, Alessandra
影响因子：
3.8
作者：
Beaver, Laura Michelle;Hooven, Louisa Ada;Giebultowicz, Jadwiga Maria
通讯作者：
Giebultowicz, Jadwiga Maria
影响因子：
10.5
作者：
Kondratov, Roman V.;Kondratova, Anna A.;Antoch, Marina P.
通讯作者：
Antoch, Marina P.
影响因子：
18.2
作者：
Allada R;Chung BY
通讯作者：
Chung BY