The essential micronutrient copper is tightly regulated in organisms, as environmental exposure or homeostasis defects can cause toxicity and neurodegenerative disease. The principal target(s) of copper toxicity have not been pinpointed, but one key effect is impaired supply of iron-sulfur (FeS) clusters to the essential protein Rli1 (ABCE1). Here, to find upstream FeS biosynthesis/delivery protein(s) responsible for this, we compared copper sensitivity of yeast-overexpressing candidate targets. Overexpression of the mitochondrial ferredoxin Yah1 produced copper hyper-resistance.55Fe turnover assays revealed that FeS integrity of Yah1 was particularly vulnerable to copper among the test proteins. Furthermore, destabilization of the FeS domain of Yah1 produced copper hypersensitivity, andYAH1overexpression rescued Rli1 dysfunction. This copper-resistance function was conserved in the human ferredoxin, Fdx2. The data indicate that the essential mitochondrial ferredoxin is an important copper target, determining a tipping point where plentiful copper supply becomes excessive. This knowledge could help in tackling copper-related diseases.

中文翻译：

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线粒体铁氧还蛋白确定细胞对铜过量的脆弱性

必需的微量营养素铜在生物体内受到严格调节，因为环境暴露或体内稳态缺陷会引起毒性和神经退行性疾病。铜毒性的主要目标尚未确定，但一个关键作用是削弱了向必需蛋白Rli1（ABCE1）提供的铁硫（FeS）簇。在这里，为了找到负责此作用的上游FeS生物合成/传递蛋白，我们比较了酵母过表达候选靶标的铜敏感性。线粒体铁氧还蛋白Yah1的过表达产生了铜的高抗性。55Fe周转分析显示Yah1的FeS完整性特别容易受测试蛋白中铜的影响。此外，Yah1 FeS结构域的不稳定导致铜超敏性，YAH1过表达挽救了Rli1功能障碍。这种铜抗性功能在人类铁氧还蛋白Fdx2中得以保留。数据表明，必需的线粒体铁氧还蛋白是重要的铜靶，决定了大量铜供应过剩的临界点。这些知识可能有助于解决与铜有关的疾病。