Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada.
Mol Biol Cell. 2013 Mar;24(6):683-91. doi: 10.1091/mbc.E12-09-0705. Epub 2013 Jan 23.
SCO1 and SCO2 are metallochaperones whose principal function is to add two copper ions to the catalytic core of cytochrome c oxidase (COX). However, affected tissues of SCO1 and SCO2 patients exhibit a combined deficiency in COX activity and total copper content, suggesting additional roles for these proteins in the regulation of cellular copper homeostasis. Here we show that both the redox state of the copper-binding cysteines of SCO1 and the abundance of SCO2 correlate with cellular copper content and that these relationships are perturbed by mutations in SCO1 or SCO2, producing a state of apparent copper overload. The copper deficiency in SCO patient fibroblasts is rescued by knockdown of ATP7A, a trans-Golgi, copper-transporting ATPase that traffics to the plasma membrane during copper overload to promote efflux. To investigate how a signal from SCO1 could be relayed to ATP7A, we examined the abundance and subcellular distribution of several soluble COX assembly factors. We found that COX19 partitions between mitochondria and the cytosol in a copper-dependent manner and that its knockdown partially rescues the copper deficiency in patient cells. These results demonstrate that COX19 is necessary for the transduction of a SCO1-dependent mitochondrial redox signal that regulates ATP7A-mediated cellular copper efflux.
SCO1 和 SCO2 是金属伴侣蛋白，其主要功能是向细胞色素 c 氧化酶 (COX) 的催化核心添加两个铜离子。然而，SCO1 和 SCO2 患者的受影响组织表现出 COX 活性和总铜含量的综合缺乏，这表明这些蛋白质在细胞内铜稳态的调节中具有额外的作用。在这里，我们表明 SCO1 的铜结合半胱氨酸的氧化还原状态和 SCO2 的丰度与细胞内铜含量相关，并且这些关系受到 SCO1 或 SCO2 突变的干扰，产生了明显的铜过载状态。SCO 患者成纤维细胞中的铜缺乏可以通过敲低 ATP7A 来挽救，ATP7A 是一种跨高尔基铜转运 ATP 酶，在铜过载时会向质膜运输以促进外排。为了研究 SCO1 的信号如何被传递到 ATP7A，我们检查了几种可溶性 COX 组装因子的丰度和亚细胞分布。我们发现 COX19 以铜依赖性的方式在线粒体和细胞质之间分配，其敲低部分挽救了患者细胞中的铜缺乏。这些结果表明，COX19 是 SCO1 依赖性线粒体氧化还原信号转导所必需的，该信号调节 ATP7A 介导的细胞铜外排。
