Mitochondrial Respiratory Chain Dysfunction in Muscle From Patients With Amyotrophic Lateral Sclerosis
Mitochondrial Respiratory Chain Dysfunction in Muscle From Patients With Amyotrophic Lateral Sclerosis
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DOI：
10.1001/archneurol.2010.128
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发表时间：
2010-07-01
影响因子：
--
通讯作者：
Moggio, Maurizio
中科院分区：
文献类型：
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作者：
Crugnola, Veronica;Lamperti, Costanza;Moggio, Maurizio
背景：肌萎缩侧索硬化症（ALS）是神经功能障碍的主要原因，尽管进行了大量研究，但其发病机制仍然难以捉摸。虽然线粒体呼吸链缺陷在几位 ALS 患者中已被描述，但其致病意义尚不清楚。目的：系统地回顾典型散发性 ALS 患者的肌肉活检标本，以寻找可能的线粒体氧化损伤。设计：肌肉标本的回顾性组织化学、生化和分子研究。地点：三级护理大学。受试者：50 名典型散发性 ALS 患者（平均年龄，55 岁）。主要结果指标：通过组织化学和生化肌肉分析评估显示明显肌肉线粒体功能障碍的患者数量。结果：组织化学数据显示 46% 的患者存在细胞色素 C 氧化酶 (COX) 阴性纤维。根据COX组织化学活性，患者分为4组：27名COX活性正常； 8 名患有轻度（100 条纤维中的 2-4 条 COX 阴性纤维），8 名患有中度（100 条中 5-10 条 COX 阴性纤维），7 名患有严重（100 条中>10 条 COX 阴性纤维）COX 缺乏。呼吸链活性的分光光度测量显示，3 名严重组织化学 COX 缺乏的患者也表现出联合酶缺陷。在 1 名患者中，在第一次活检 9 个月后进行的第二次活检中，COX 缺乏症恶化。在严重 COX 缺乏的患者中，一名患者的 SOD1 基因出现新突变，另一名患者的 TARDBP 基因出现突变，第三名生化证实 COX 缺乏的患者通过 Southern 印迹分析可检测到多个线粒体 DNA 缺失。 结论：我们的数据证实，COX 阴性纤维的组织化学发现在散发性 ALS 患者的骨骼肌中很常见。我们没有发现氧化缺陷的严重程度与患者年龄或疾病持续时间之间的相关性。然而，唯一接受第二次肌肉活检的患者确实显示出症状严重程度与呼吸链缺陷恶化之间存在相关性。 7 名患者的氧化缺陷非常严重，足以支持线粒体功能障碍在该疾病的发病机制中发挥作用的假设。
Background: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear.Objective: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment.Design: Retrospective histochemical, biochemical, and molecular studies of muscle specimens.Setting: Tertiary care university.Subjects: Fifty patients with typical sporadic ALS (mean age, 55 years).Main Outcome Measure: Number of patients showing a clear muscle mitochondrial dysfunction assessed through histochemical and biochemical muscle analysis.Results: Histochemical data showed cytochrome c oxidase (COX)-negative fibers in 46% patients. Based on COX histochemical activity, patients fell into 4 groups: 27 had normal COX activity; and 8 had mild (2-4 COX-negative fibers of 100 fibers), 8 had moderate (5-10 COX-negative fibers of 100), and 7 had severe (>10 COX-negative fibers of 100) COX deficiency. Spectrophotometric measurement of respiratory chain activities showed that 3 patients with severe histochemical COX deficiency also showed combined enzyme defects. In 1 patient, COX deficiency worsened in a second biopsy taken 9 months after the first. Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis.Conclusions: Our data confirm that the histochemical finding of COX-negative fibers is common in skeletal muscle from patients with sporadic ALS. We did not find a correlation between severity of the oxidative defect and age of the patients or duration of the disease. However, the only patient who underwent a second muscle biopsy did show a correlation between severity of symptoms and worsening of the respiratory chain defect. In 7 patients, the oxidative defect was severe enough to support the hypothesis that mitochondrial dysfunction must play a role in the pathogenesis of the disease.