In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space.
In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space.
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DOI：
10.1523/jneurosci.1965-11.2011
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发表时间：
2011-11-02
期刊：
影响因子：
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通讯作者：
Manfredi G
中科院分区：
文献类型：
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作者：
Igoudjil A;Magrané J;Fischer LR;Kim HJ;Hervias I;Dumont M;Cortez C;Glass JD;Starkov AA;Manfredi G
铜锌超氧化物歧化酶(SOD1)基因突变与家族性肌萎缩侧索硬化症(ALS)相关。突变的SOD1通过毒性获得功能机制，引起一系列复杂的病理事件，导致选择性运动神经元变性。线粒体功能障碍是突变体SOD1众所周知的毒性效应之一，但其机制才刚刚开始阐明。突变体SOD1的一部分定位于线粒体，主要聚集在外膜和膜间隙(IMS)内。在培养细胞中的证据表明，IMS中的突变SOD1会导致线粒体功能障碍，并损害细胞活力。因此，为了测试其在体内的致病作用，我们建立了选择性靶向线粒体IMS的表达G93A突变体或野生型(WT)人SOD1的转基因小鼠(mito-SOD1)。我们证明Mito-SOD1正确地定位在IMS中，在那里它寡聚并获得酶活性。Mito-G93ASOD1小鼠，而不是Mito-WTSOD1小鼠，会发展成一种进行性疾病，其特征是体重减轻、肌肉无力、脑萎缩和运动障碍，这在雌性小鼠中更为严重。这些症状与脊髓运动神经元数量减少和线粒体生物能量学受损有关，其特征是细胞色素氧化酶活性降低和钙处理缺陷。然而，没有证据表明肌肉失神经，这是ALS的主要病理特征。综上所述，我们的研究结果表明，线粒体IMS中的突变SOD1会导致线粒体功能障碍和神经变性，但本身并不足以导致完全的ALS表型，这需要定位于其他细胞间隔的突变SOD1的参与。
Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes a complex array of pathological events, through toxic gain of function mechanisms, leading to selective motor neuron degeneration. Mitochondrial dysfunction is among the well-established toxic effects of mutant SOD1, but its mechanisms are just starting to be elucidated. A portion of mutant SOD1 is localized in mitochondria, where it accumulates mostly on the outer membrane and inside the intermembrane space (IMS). Evidence in cultured cells suggests that mutant SOD1 in the IMS causes mitochondrial dysfunction and compromises cell viability. Therefore, to test its pathogenic role in vivo we generated transgenic mice expressing G93A mutant or wild type (WT) human SOD1 targeted selectively to the mitochondrial IMS (mito-SOD1). We show that mito-SOD1 is correctly localized in the IMS, where it oligomerizes and acquires enzymatic activity. Mito-G93ASOD1 mice, but not mito-WTSOD1 mice, develop a progressive disease characterized by body weight loss, muscle weakness, brain atrophy, and motor impairment, which is more severe in females. These symptoms are associated with reduced spinal motor neuron counts and impaired mitochondrial bioenergetics, characterized by decreased cytochrome oxidase activity and defective calcium handling. However, there is no evidence of muscle denervation, a cardinal pathological feature of ALS. Taken together, our findings indicate that mutant SOD1 in the mitochondrial IMS causes mitochondrial dysfunction and neurodegeneration, but per se it is not sufficient to cause a full-fledged ALS phenotype, which requires the participation of mutant SOD1 localized in other cellular compartments.