Defective mitochondrial dynamics is an early event in skeletal muscle of an amyotrophic lateral sclerosis mouse model.
Defective mitochondrial dynamics is an early event in skeletal muscle of an amyotrophic lateral sclerosis mouse model.
复制标题
DOI：
10.1371/journal.pone.0082112
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Luo G;Yi J;Ma C;Xiao Y;Yi F;Yu T;Zhou J
线粒体是动态的细胞器，不断进行融合和分裂以维持其正常功能。线粒体动力学的损伤与各种神经退行性疾病有关。肌萎缩性侧索硬化症（ALS）是一种以运动神经元死亡和肌肉萎缩为特征的成人发病的神经肌肉退行性疾病。肌萎缩侧索硬化症的发病和进展明显涉及运动神经元变性，但越来越多的证据表明，原发性肌肉病理也可能参与其中。在这里，我们研究了线粒体动力学在ALS小鼠模型（G93 A）窝藏超氧化物歧化酶突变（SOD 1G 93 A）的活骨骼肌。使用共聚焦显微镜结合过表达的靶向光激活荧光蛋白，我们发现异常的线粒体动力学在发病前的年轻G93 A小鼠骨骼肌。我们进一步证明，在正常小鼠的骨骼肌中，突变体SOD 1G 93 A的过表达诱导了线粒体动力学的类似异常，表明在没有运动神经元变性的情况下，SOD 1突变驱动ALS样肌肉病理学。突变体SOD 1G 93 A在肌肉线粒体内形成聚集体，并导致线粒体网络的碎片化以及线粒体去极化。在正常肌肉中的线粒体膜电位的部分去极化的羰基氰化物对三氟甲氧基苯腙（FCCP）引起的线粒体动力学的异常，在SOD 1G 93 A模型肌肉相似。一种特异的线粒体分裂抑制剂（Mdivi-1）逆转了SOD 1G 93 A对线粒体动力学的作用，表明SOD 1G 93 A可能促进线粒体分裂过程。我们的研究结果表明，线粒体内的突变体SOD 1G 93 A的积累，线粒体膜电位的去极化和异常的线粒体动力学是因果联系的，并导致内在的肌肉病理，这发生在ALS的过程中的早期，并可能积极促进ALS的进展。
Mitochondria are dynamic organelles that constantly undergo fusion and fission to maintain their normal functionality. Impairment of mitochondrial dynamics is implicated in various neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an adult-onset neuromuscular degenerative disorder characterized by motor neuron death and muscle atrophy. ALS onset and progression clearly involve motor neuron degeneration but accumulating evidence suggests primary muscle pathology may also be involved. Here, we examined mitochondrial dynamics in live skeletal muscle of an ALS mouse model (G93A) harboring a superoxide dismutase mutation (SOD1G93A). Using confocal microscopy combined with overexpression of mitochondria-targeted photoactivatable fluorescent proteins, we discovered abnormal mitochondrial dynamics in skeletal muscle of young G93A mice before disease onset. We further demonstrated that similar abnormalities in mitochondrial dynamics were induced by overexpression of mutant SOD1G93A in skeletal muscle of normal mice, indicating the SOD1 mutation drives ALS-like muscle pathology in the absence of motor neuron degeneration. Mutant SOD1G93A forms aggregates inside muscle mitochondria and leads to fragmentation of the mitochondrial network as well as mitochondrial depolarization. Partial depolarization of mitochondrial membrane potential in normal muscle by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) caused abnormalities in mitochondrial dynamics similar to that in the SOD1G93A model muscle. A specific mitochondrial fission inhibitor (Mdivi-1) reversed the SOD1G93A action on mitochondrial dynamics, indicating SOD1G93A likely promotes mitochondrial fission process. Our results suggest that accumulation of mutant SOD1G93A inside mitochondria, depolarization of mitochondrial membrane potential and abnormal mitochondrial dynamics are causally linked and cause intrinsic muscle pathology, which occurs early in the course of ALS and may actively promote ALS progression.
登录
查看更多内容
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
7.4
作者：
Gomez-Lazaro, Maria;Bonekamp, Nina A.;Schrader, Michael
通讯作者：
Schrader, Michael
影响因子：
11.4
作者：
Barsoum, Mark J.;Yuan, Hua;Bossy-Wetzel, Ella
通讯作者：
Bossy-Wetzel, Ella
影响因子：
14.5
作者：
Krasnianski, A;Deschauer, M;Zierz, S
通讯作者：
Zierz, S