Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons.
Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons.
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DOI：
10.1523/jneurosci.1233-11.2012
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发表时间：
2012-01-04
期刊：
影响因子：
--
通讯作者：
Manfredi G
中科院分区：
文献类型：
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作者：
Magrané J;Sahawneh MA;Przedborski S;Estévez ÁG;Manfredi G
铜锌超氧化物歧化酶(SOD1)基因突变可导致家族性肌萎缩侧索硬化症(FALS)，这是一种迅速致死的运动神经元病。突变型SOD1对运动神经元具有多向毒性作用，其中线粒体功能障碍被认为是运动神经元死亡的原因之一。线粒体在神经元中是高度动态的；它们不断地被融合重塑，并沿着神经突起移动，以定位在高能量利用的位置，如突触。神经肌肉接头线粒体异常堆积的发现，提示运动神经元线粒体动力学受损可能参与发病机制。我们通过对表达突变型或野生型人SOD1的转基因大鼠运动神经元中的光可切换荧光mitoDendra的实时成像显微镜来解决这一假说。我们证明突变的SOD1运动神经元已经损害了轴突和细胞体中的线粒体融合。线粒体也表现出逆行轴突运输的选择性损害，运动频率和速度降低。融合和运输缺陷与线粒体体积变小、密度降低和线粒体膜电位缺陷有关。此外，在体外，线粒体在运动神经元之间突触的错误定位与突触数量、结构和功能的异常相关。动力学异常是突变型SOD1运动神经元线粒体特有的，因为它们在野生型SOD1运动神经元中不存在，它们不涉及其他细胞器，也不在皮质神经元中发现。综上所述，这些结果提示线粒体动力学受损可能是SOD-FALS运动神经元选择性变性的原因之一。
Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Taken together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS.