Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065, USA.
Antioxid Redox Signal. 2010 Nov 1;13(9):1375-84. doi: 10.1089/ars.2010.3212.
Cu, Zn, superoxide dismutase (SOD1) is a ubiquitous enzyme localized in multiple cellular compartments, including mitochondria, where it concentrates in the intermembrane space (IMS). Similar to other small IMS proteins, the import and retention of SOD1 in the IMS is linked to its folding and maturation, involving the formation of critical intra- and intermolecular disulfide bonds. Therefore, the cysteine residues of SOD1 play a fundamental role in its IMS localization. IMS import of SOD1 involves its copper chaperone, CCS, whose mitochondrial distribution is regulated by the Mia40/Erv1 disulfide relay system in a redox-dependent manner: CCS promotes SOD1 maturation and retention in the IMS. The function of SOD1 in the IMS is still unknown, but it is plausible that it serves to remove superoxide released from the mitochondrial respiratory chain. Mutations in SOD1 cause familial amyotrophic lateral sclerosis (ALS), whose pathologic features include mitochondrial bioenergetic dysfunction. Mutant SOD1 localization in the IMS is not dictated by oxygen concentration and the Mia40/Erv1 system, but is primarily dependent on aberrant protein folding and aggregation. Mutant SOD1 localization and aggregation in the IMS might cause the mitochondrial abnormalities observed in familial ALS and could play a significant role in disease pathogenesis.
铜锌超氧化物歧化酶（SOD1）是一种广泛存在的酶，定位于多个细胞区室，包括线粒体，在那里它集中在膜间隙（IMS）中。与其他小 IMS 蛋白类似，SOD1 的导入和保留在 IMS 中与其折叠和成熟有关，涉及关键的分子内和分子间二硫键的形成。因此，SOD1 的半胱氨酸残基在其 IMS 定位中起着重要作用。SOD1 的 IMS 导入涉及其铜伴侣蛋白 CCS，其线粒体分布受 Mia40/Erv1 二硫键中继系统以依赖氧化还原的方式调节：CCS 促进 SOD1 在 IMS 中的成熟和保留。SOD1 在 IMS 中的功能尚不清楚，但它可能有助于去除线粒体呼吸链释放的超氧化物。SOD1 突变导致家族性肌萎缩侧索硬化症（ALS），其病理特征包括线粒体生物能功能障碍。突变 SOD1 在 IMS 中的定位不受氧浓度和 Mia40/Erv1 系统的支配，而是主要依赖于异常的蛋白质折叠和聚集。突变 SOD1 在 IMS 中的定位和聚集可能导致家族性 ALS 中观察到的线粒体异常，并可能在疾病发病机制中发挥重要作用。
