Elesclomol restores mitochondrial function in genetic models of copper deficiency.
Elesclomol restores mitochondrial function in genetic models of copper deficiency.
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DOI：
10.1073/pnas.1806296115
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发表时间：
2018-08-07
影响因子：
11.1
通讯作者：
Gohil VM
中科院分区：
文献类型：
--
作者：
Soma S;Latimer AJ;Chun H;Vicary AC;Timbalia SA;Boulet A;Rahn JJ;Chan SSL;Leary SC;Kim BE;Gitlin JD;Gohil VM
铜传递到细胞色素c氧化酶（CcO）所需基因的遗传致病性突变扰乱线粒体能量代谢并导致致命的线粒体疾病。先前尝试通过直接补充铜来治疗这些突变的人类患者并不成功，可能是因为铜递送到线粒体的效率低下。我们进行了一项有针对性的研究，以确定可以有效地通过生物膜运输铜的化合物，并确定了埃雷斯克洛莫尔（ES），一种正在研究的抗癌药物，作为最有效的铜递送剂。ES通过增加细胞和线粒体铜含量，在酵母、斑马鱼和哺乳动物缺铜模型中恢复CcO功能。因此，我们的研究提供了一种重新利用这种抗癌药物治疗铜代谢障碍的可能性。铜是线粒体呼吸链末端酶细胞色素c氧化酶（CcO）的重要辅助因子。一些编码铜传递到CcO所需蛋白质的基因的遗传性功能缺失突变导致受影响婴儿的CcO活性降低和严重的病理状况。在COA6和SCO2这两个基因突变的患者细胞中，补充铜可以恢复CcO功能，这提示了一种潜在的治疗方法。然而，直接补充铜在人类患者中没有治疗效果，强调需要确定高效的铜转运药物。通过使用基于候选药物的方法，我们确定了一种正在研究的抗癌药物——埃雷斯克洛莫尔（ES），它通过增加线粒体铜含量和恢复CcO活性来拯救coa6缺乏的酵母细胞的呼吸缺陷。ES还能挽救其他酵母菌铜代谢突变体的呼吸缺陷，这表明它具有更广泛的适用性。低纳摩尔浓度的ES可在斑马鱼缺铜模型和一系列缺铜哺乳动物细胞（包括来自SCO2突变患者的细胞）中恢复CcO含铜亚基。这些发现表明，ES可以通过模拟缺失的铜转运蛋白和伴侣蛋白的功能，恢复细胞内铜稳态，并可能在治疗人类铜代谢障碍方面具有潜力。
Inherited pathogenic mutations in genes required for copper delivery to cytochrome c oxidase (CcO) perturb mitochondrial energy metabolism and result in fatal mitochondrial disease. A prior attempt to treat human patients with these mutations by direct copper supplementation was not successful, possibly because of inefficient copper delivery to the mitochondria. We performed a targeted search to identify compounds that can efficiently transport copper across biological membranes and identified elesclomol (ES), an investigational anticancer drug, as the most efficient copper delivery agent. ES rescues CcO function in yeast, zebrafish, and mammalian models of copper deficiency by increasing cellular and mitochondrial copper content. Thus, our study offers a possibility of repurposing this anticancer drug for the treatment of disorders of copper metabolism. Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.
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