Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials
Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials
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DOI：
10.1073/pnas.0605814103
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发表时间：
2006-09-12
影响因子：
11.1
通讯作者：
Carri, Maria Teresa
中科院分区：
文献类型：
--
作者：
Ferri, Alberto;Cozzolino, Mauro;Carri, Maria Teresa
最近的研究表明，家族性肌萎缩侧索硬化症突变型铜，锌超氧化物歧化酶（SOD 1）的毒性来自于其选择性募集到线粒体。在这里，我们证明了12个不同的家族ALS突变体SOD1的生物物理特性有很大的不同与运动神经元细胞的线粒体在更大程度上比野生型SOD1，这种效果可能取决于半胱氨酸残基的氧化。我们进一步证明，突变SOD 1蛋白与线粒体往往形成交联的低聚物，它们的存在会导致这些细胞器的氧化还原状态的转变，并导致呼吸复合物受损。观察到这样一组不同的突变SOD 1蛋白在运动神经元细胞的线粒体中表现得如此相似，而与野生型SOD 1如此不同，这表明这种行为可以解释ALS突变SOD 1蛋白的毒性，其导致运动神经元死亡。
Recent studies suggest that the toxicity of familial amyotrophic lateral sclerosis mutant Cu, Zn superoxide dismutase (SOD1) arises from its selective recruitment to mitochondria. Here we demonstrate that each of 12 different familial ALS-mutant SOD1s with widely differing biophysical properties are associated with mitochondria of motoneuronal cells to a much greater extent than wild-type SOD1, and that this effect may depend on the oxidation of Cys residues. We demonstrate further that mutant SOD1 proteins associated with the mitochondria tend to form cross-linked oligomers and that their presence causes a shift in the redox state of these organelles and results in impairment of respiratory complexes. The observation that such a diverse set of mutant SOD1 proteins behave so similarly in mitochondria of motoneuronal cells and so differently from wild-type SOD1 suggests that this behavior may explain the toxicity of ALS-mutant SOD1 proteins, which causes motor neurons to die.