Elesclomol restores mitochondrial function in genetic models of copper deficiency

被引:74
作者
Soma, Shivatheja [1 ]
Latimer, Andrew J. [2 ]
Chun, Haarin [3 ]
Vicary, Alison C. [1 ]
Timbalia, Shrishiv A. [1 ]
Boulet, Aren [4 ]
Rahn, Jennifer J. [5 ]
Chan, Sherine S. L. [5 ]
Leary, Scot C. [4 ]
Kim, Byung-Eun [3 ]
Gitlin, Jonathan D. [2 ]
Gohil, Vishal M. [1 ]
机构
[1] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA
[2] Marine Biol Lab, Eugene Bell Ctr Regenerat Biol & Tissue Engn, Woods Hole, MA 02543 USA
[3] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA
[4] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 5E5, Canada
[5] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA
基金
美国国家卫生研究院; 加拿大健康研究院;
关键词
copper; mitochondria; elesclomol; cytochrome c oxidase; CYTOCHROME-C-OXIDASE; BINDING PROTEIN; HYPERTROPHIC CARDIOMYOPATHY; DRUG ELESCLOMOL; SCO2; MUTATIONS; COA6; DISEASE; BIOGENESIS; MATRIX;
D O I
10.1073/pnas.1806296115
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:8161 / 8166
页数:6
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