ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression.
ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression.
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DOI：
10.1016/j.phrs.2018.09.008
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发表时间：
2018-12
影响因子：
9.3
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Xiao Y;Karam C;Yi J;Zhang L;Li X;Yoon D;Wang H;Dhakal K;Ramlow P;Yu T;Mo Z;Ma J;Zhou J
在肌萎缩侧索硬化症（ALS）中，线粒体功能障碍和氧化应激形成恶性循环，促进神经退行性变和肌肉萎缩。为了量化线粒体功能的疾病阶段依赖性变化及其与活性氧（ROS）产生的关系，我们生成了携带人类ALS突变SOD1G93A和mt-cpYFP转基因的双转基因小鼠（G93A/cpYFP），其中mt-cpYFP在个体线粒体水平检测ROS相关线粒体事件的动态变化。与野生型小鼠相比，SOD1G93A（G93A）小鼠肌肉中的线粒体活性在ALS症状（2月龄）出现之前表现出闪烁频率增加，而ALS症状（4月龄）的出现与线粒体闪信号动力学特性的剧烈变化相关，半峰全持续时间（FDHM）延长。使用荧光探针 MitoSOX™ Red 和 ROS Brite™ 570 证实了 SOD1G93A 小鼠骨骼肌中胞质 ROS 水平的升高。G93A 肌肉亚细胞线粒体分级的免疫印迹分析显示，亲环蛋白 D (CypD) 的表达水平升高，而亲环蛋白 D (CypD) 是线粒体通透性转换孔 (mPTP) 的调节成分，在 4 个月大时，但在 4 个月大时没有增加2个月。野生型小鼠骨骼肌中 SOD1G93A 的瞬时过表达直接促进线粒体 ROS 产生，在没有运动神经元轴突撤退的情况下，线粒体活性增强。值得注意的是，使用 CypD 抑制剂环孢菌素 A (CsA) 可以减弱 SOD1G93A 诱导的线粒体活性。与 SOD1G93A 转基因小鼠的观察结果类似，在 SOD1G93A 短暂过度表达后，骨骼肌中 CypD 的表达水平也有所增加。总体而言，这项研究揭示了线粒体功能的疾病阶段依赖性变化，与 CypD 依赖性 mPTP 打开相关。在没有运动神经元轴突撤退的情况下，ALS 突变 SOD1G93A 直接导致线粒体功能障碍。
In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction and oxidative stress form a vicious cycle that promotes neurodegeneration and muscle wasting. To quantify the diseasestage-dependent changes of mitochondrial function and their relationship to the generation of reactive oxygen species (ROS), we generated double transgenic mice (G93A/cpYFP) that carry human ALS mutation SOD1G93A and mt-cpYFP transgenes, in which mt-cpYFP detects dynamic changes of ROS-related mitoflash events at individual mitochondria level. Compared with wild type mice, mitoflash activity in the SOD1G93A (G93A) mouse muscle showed an increased flashing frequency prior to the onset of ALS symptom (at the age of 2 months), whereas the onset of ALS symptoms (at the age of 4 months) is associated with drastic changes in the kinetics property of mitoflash signal with prolonged full duration at half maximum (FDHM). Elevated levels of cytosolic ROS in skeletal muscle derived from the SOD1G93A mice were confirmed with fluorescent probes, MitoSOX™ Red and ROS Brite™ 570. Immunoblotting analysis of subcellular mitochondrial fractionation of G93A muscle revealed an increased expression level of cyclophilin D (CypD), a regulatory component of the mitochondrial permeability transition pore (mPTP), at the age of 4 months but not at the age of 2 months. Transient overexpressing of SOD1G93A in skeletal muscle of wild type mice directly promoted mitochondrial ROS production with an enhanced mitoflash activity in the absence of motor neuron axonal withdrawal. Remarkably, the SOD1G93A-induced mitoflash activity was attenuated by the application of cyclosporine A (CsA), an inhibitor of CypD. Similar to the observation with the SOD1G93A transgenic mice, an increased expression level of CypD was also detected in skeletal muscle following transient overexpression of SOD1G93A. Overall, this study reveals a disease-stage-dependent change in mitochondrial function that is associated with CypD-dependent mPTP opening; and the ALS mutation SOD1G93A directly contributes to mitochondrial dysfunction in the absence of motor neuron axonal withdrawal.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
DOI：
10.1073/pnas.0605814103
发表时间：
2006-09-12
影响因子：
11.1
作者：
Ferri, Alberto;Cozzolino, Mauro;Carri, Maria Teresa
通讯作者：
Carri, Maria Teresa
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
5
作者：
Bernardi, Paolo;Di Lisa, Fabio
通讯作者：
Di Lisa, Fabio
影响因子：
64.8
作者：
Baines, CP;Kaiser, RA;Molkentin, JD
通讯作者：
Molkentin, JD