Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery.
Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery.
复制标题
DOI：
10.1016/j.jbc.2022.102139
复制
发表时间：
2022-07
影响因子：
4.8
通讯作者：
Gohil, Vishal M.
中科院分区：
文献类型：
--
作者：
Garza, Natalie M.;Zulkifli, Mohammad;Gohil, Vishal M.
铜（Cu）和铁（Fe）是氧化还原活性金属，可作为许多必需细胞酶的辅因子。这些金属的细胞内稳态的破坏导致衰弱和经常致命的人类疾病，如门克斯病和弗里德赖希共济失调。最近，我们报道了一种正在研究的抗癌药物elesclomol（ES），可以将Cu输送到关键的线粒体铜酶，并有可能重新用于治疗铜缺乏症。在这里，我们试图确定ES和ES-Cu络合物在不同细胞内隔室中向铜酶递送Cu的特异性。使用酵母遗传学，亚细胞分级分离，电感耦合等离子体质谱法为基础的金属测量的组合，我们表明，ES和ES-Cu治疗的结果在细胞和线粒体铁含量的增加，沿着预期的增加铜。使用酵母突变体的铜和铁转运蛋白，我们表明，ES为基础的海拔在细胞铁水平是独立的主要细胞铜进口商，但依赖于铁进口商FTR 1和它的合作伙伴Fet 3，多铜氧化酶。由于Fet 3在高尔基体腔中被金属化，我们试图揭示Fet 3从ES接收Cu的机制。使用酵母敲除参与铜传递到Fet 3的基因，我们确定ES可以绕过Atx 1，金属伴侣参与铜传递到高尔基体膜铜泵，Ccc 2，但不是Ccc 2本身。综上所述，我们的研究提供了一种机制，ES分配铜在细胞和影响细胞和线粒体铁稳态。
Copper (Cu) and iron (Fe) are redox-active metals that serve as cofactors for many essential cellular enzymes. Disruption in the intracellular homeostasis of these metals results in debilitating and frequently fatal human disorders, such as Menkes disease and Friedreich’s ataxia. Recently, we reported that an investigational anticancer drug, elesclomol (ES), can deliver Cu to critical mitochondrial cuproenzymes and has the potential to be repurposed for the treatment of Cu deficiency disorders. Here, we sought to determine the specificity of ES and the ES-Cu complex in delivering Cu to cuproenzymes in different intracellular compartments. Using a combination of yeast genetics, subcellular fractionation, and inductively coupled plasma-mass spectrometry–based metal measurements, we showed that ES and ES-Cu treatment results in an increase in cellular and mitochondrial Fe content, along with the expected increase in Cu. Using yeast mutants of Cu and Fe transporters, we demonstrate that ES-based elevation in cellular Fe levels is independent of the major cellular Cu importer but is dependent on the Fe importer Ftr1 and its partner Fet3, a multicopper oxidase. As Fet3 is metalated in the Golgi lumen, we sought to uncover the mechanism by which Fet3 receives Cu from ES. Using yeast knockouts of genes involved in Cu delivery to Fet3, we determined that ES can bypass Atx1, a metallochaperone involved in Cu delivery to the Golgi membrane Cu pump, Ccc2, but not Ccc2 itself. Taken together, our study provides a mechanism by which ES distributes Cu in cells and impacts cellular and mitochondrial Fe homeostasis.
登录
查看更多内容
影响因子：
12.3
作者：
Eide DJ;Clark S;Nair TM;Gehl M;Gribskov M;Guerinot ML;Harper JF
通讯作者：
Harper JF
影响因子：
4.8
作者：
Askwith, CC;Kaplan, J
通讯作者：
Kaplan, J
影响因子：
2.7
作者：
Chen, Shoujun;Sun, Lijun;Sonderfan, Andrew
通讯作者：
Sonderfan, Andrew
影响因子：
3.5
作者：
Grimes, A;Hearn, CJ;Mercer, JFB
通讯作者：
Mercer, JFB
影响因子：
4.1
作者：
Hassett, R;Dix, DR;Kosman, DJ
通讯作者：
Kosman, DJ