School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
Cell Chem Biol. 2017 Oct 19;24(10):1228-1237.e3. doi: 10.1016/j.chembiol.2017.08.005. Epub 2017 Aug 31.
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. Fe 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, and YAH1 overexpression 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.
必需微量营养素铜在生物体中受到严格调控，因为环境暴露或体内平衡缺陷会导致毒性和神经退行性疾病。铜毒性的主要靶标尚未确定，但一个关键影响是铁硫 (FeS) 簇向必需蛋白 Rli1 (ABCE1) 的供应受损。在这里，为了找到导致这种情况的上游 FeS 生物合成/输送蛋白，我们比较了酵母过表达候选靶标的铜敏感性。过表达线粒体铁氧还蛋白 Yah1 可产生铜超敏性。铁周转测定表明，在测试蛋白中，Yah1 的 FeS 完整性对铜特别敏感。此外，Yah1 的 FeS 结构域的不稳定性会导致铜超敏性，并且 YAH1 的过表达可挽救 Rli1 功能障碍。这种铜抗性功能在人类铁氧还蛋白 Fdx2 中是保守的。这些数据表明，必需的线粒体铁氧还蛋白是铜的重要靶标，决定了大量铜供应变得过量的临界点。这一知识有助于解决与铜相关的疾病。
