Beal M F
Neurology Service/WRN 408, Massachusetts General Hospital and Harvard Medical School, 32 Fruit Street, Boston, MA 02114, USA.
Biochim Biophys Acta. 1998 Aug 10;1366(1-2):211-23. doi: 10.1016/s0005-2728(98)00114-5.
A potential pivotal role for mitochondrial dysfunction in neurodegenerative diseases is gaining increasing acceptance. Mitochondrial dysfunction leads to a number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Neurodegenerative diseases of widely disparate genetic etiologies may share mitochondrial dysfunction as a final common pathway. Recent studies using cybrid cell lines suggest that sporadic Alzheimer's disease is associated with a deficiency of cytochrome oxidase. Friedreich's ataxia is caused by an expanded GAA repeat resulting in dysfunction of frataxin, a nuclear encoded mitochondrial protein involved in mitochondrial iron transport. This results in increased mitochondrial iron and oxidative damage. Familial amyotrophic lateral sclerosis is associated with point mutations in superoxide dismutase, which may lead to increased generation of free radicals and thereby contribute to mitochondrial dysfunction. Huntington's disease (HD) is caused by an expanded CAG repeat in an unknown protein termed huntingtin. The means by which this leads to energy impairment is unclear, however studies in both HD patients and a transgenic mouse model show evidence of bioenergetic defects. Mitochondrial dysfunction leads to oxidative damage which is well documented in several neurodegenerative diseases. Therapeutic approaches include methods to buffer intracellular ATP and to scavenge free radicals.
线粒体功能障碍在神经退行性疾病中可能发挥的关键作用正日益得到认可。线粒体功能障碍会导致一系列有害后果，包括钙缓冲受损、自由基生成、线粒体通透性转换的激活以及继发性兴奋毒性。病因广泛不同的神经退行性疾病可能都存在线粒体功能障碍这一最终共同途径。最近使用细胞融合体细胞系进行的研究表明，散发性阿尔茨海默病与细胞色素氧化酶缺乏有关。弗里德赖希共济失调是由GAA重复序列扩增引起的，导致frataxin功能障碍，frataxin是一种参与线粒体铁转运的核编码线粒体蛋白。这会导致线粒体铁增加和氧化损伤。家族性肌萎缩侧索硬化症与超氧化物歧化酶的点突变有关，这可能导致自由基生成增加，从而导致线粒体功能障碍。亨廷顿舞蹈病（HD）是由一种名为亨廷顿蛋白的未知蛋白质中的CAG重复序列扩增引起的。然而，目前尚不清楚这是如何导致能量受损的，不过对HD患者和转基因小鼠模型的研究都显示出生物能量缺陷的证据。线粒体功能障碍会导致氧化损伤，这在几种神经退行性疾病中都有充分记录。治疗方法包括缓冲细胞内ATP和清除自由基的方法。
