Impairment of axonal transport of mitochondria and axonal degeneration induced by free radicals

维持神经元功能和形态所需的能量由线粒体提供。神经元有轴突，因此，为了提供能量，线粒体应该通过轴突运输来进行。当线粒体在轴突中的运输受损时，就会发生各种病理情况。尤其是轴突变性与线粒体转运功能障碍密切相关。线粒体通过有氧呼吸提供三磷酸腺苷的过程中释放大量的自由基。一氧化氮是一种自由基，具有细胞毒性，可被线粒体酶超氧化物歧化酶(SOD)清除。本研究探讨了自由基对线粒体轴突运输的影响。使用视频增强显微镜进行实验。一氧化氮供体NOC18抑制线粒体的顺行和逆行轴突运输。超氧化物歧化酶抑制剂二乙基二硫代氨基甲酸酯也抑制线粒体运输并诱导轴突变性。一氧化氮增加了线粒体的运输。因此，内源性一氧化氮会抑制线粒体的运输。羟基自由基清除剂二甲基硫脲对线粒体转运无影响，提示它们与线粒体转运障碍无关。这可能是因为羟基自由基只能存在微秒。目前的研究表明，内源性和外源性自由基抑制了线粒体的运输。由于线粒体转运障碍会导致轴突变性，自由基的异常增加可能会损害线粒体的转运，导致神经元变性。

Energy required for keeping function and morphology in neurons are provided by mitochondria. Neurons have axons, therefore, for providing energy, mitochondria should be carried by axonal transport. When transport of mitochondria in axon is impaired, various pathological conditions occur. Especially, axonal degeneration is closely related to impairment of mitochondrial transport. Mitochondria release amounts of free radicals during providing ATP through aerobic respiration. Nitric oxide, one of free radicals, has cellular toxicity and is removed by superoxide dismutase (SOD), a mitochondrial enzyme. The present study examined the influence of free radicals on axonal transport of mitochondria. Video-enhanced microscopy was used for experiments. The nitric oxide donor NOC18 inhibited anterograde and retrograde axonal transport of mitochondria. The SOD inhibitor diethyldithio carbamate also inhibited mitochondrial transport and induced axonal degeneration. The nitric oxide increased mitochondrial transport. Thus, intrinsic nitric oxide tonically inhibits mitochondrial transport. The hydroxyl radical scavenger dimethyl thiourea did not affect mitochondrial transport, suggesting that they are not related to impairment of mitochondrial transport. This may be because hydroxyl radicals can exist for only microseconds. The present study indicates that intrinsic and extrinsic free radicals inhibit mitochondrial transport. Since impairment of mitochondrial transport leads to axonal degeneration, abnormally increased free radicals may impair mitochondrial transport, causing degeneration in neurons.