PMID- 30038027 OWN - NLM STAT- MEDLINE DCOM- 20180920 LR - 20201209 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 32 DP - 2018 Aug 7 TI - Elesclomol restores mitochondrial function in genetic models of copper deficiency. PG - 8161-8166 LID - 10.1073/pnas.1806296115 [doi] AB - 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. CI - Copyright (c) 2018 the Author(s). Published by PNAS. FAU - Soma, Shivatheja AU - Soma S AD - Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843. FAU - Latimer, Andrew J AU - Latimer AJ AD - Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA 02543. FAU - Chun, Haarin AU - Chun H AD - Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742. FAU - Vicary, Alison C AU - Vicary AC AD - Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843. FAU - Timbalia, Shrishiv A AU - Timbalia SA AD - Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843. FAU - Boulet, Aren AU - Boulet A AD - Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. FAU - Rahn, Jennifer J AU - Rahn JJ AD - Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425. FAU - Chan, Sherine S L AU - Chan SSL AD - Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425. FAU - Leary, Scot C AU - Leary SC AUID- ORCID: 0000-0001-8488-7822 AD - Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. FAU - Kim, Byung-Eun AU - Kim BE AD - Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742. FAU - Gitlin, Jonathan D AU - Gitlin JD AD - Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA 02543. FAU - Gohil, Vishal M AU - Gohil VM AUID- ORCID: 0000-0002-9920-2563 AD - Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; vgohil@tamu.edu. LA - eng GR - R01 DK110195/DK/NIDDK NIH HHS/United States GR - MOP 133562/CIHR/Canada GR - R01 GM111672/GM/NIGMS NIH HHS/United States GR - R01 DK044464/DK/NIDDK NIH HHS/United States GR - R37 DK044464/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180723 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antineoplastic Agents) RN - 0 (COA6 protein, human) RN - 0 (Carrier Proteins) RN - 0 (Coenzymes) RN - 0 (Copper Transporter 1) RN - 0 (Drugs, Investigational) RN - 0 (Hydrazines) RN - 0 (Membrane Transport Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (Molecular Chaperones) RN - 0 (SCO2 protein, human) RN - 0 (Slc31a1 protein, zebrafish) RN - 0 (Zebrafish Proteins) RN - 6UK191M53P (elesclomol) RN - 789U1901C5 (Copper) RN - EC 1.9.3.1 (Electron Transport Complex IV) SB - IM MH - Animals MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Biological Transport/genetics MH - Carrier Proteins/genetics MH - Cell Line MH - Coenzymes/deficiency MH - Copper/*deficiency/therapeutic use MH - Copper Transporter 1 MH - Dietary Supplements MH - Disease Models, Animal MH - Drug Repositioning MH - Drugs, Investigational/*pharmacology/therapeutic use MH - Electron Transport Complex IV/*metabolism MH - Fibroblasts MH - Humans MH - Hydrazines/*pharmacology/therapeutic use MH - Membrane Transport Proteins/genetics MH - Metabolism, Inborn Errors/drug therapy/genetics/metabolism MH - Mitochondria/*drug effects/metabolism MH - Mitochondrial Proteins/genetics MH - Molecular Chaperones MH - Mutagenesis, Site-Directed MH - Mutation MH - Rats MH - Saccharomyces cerevisiae MH - Zebrafish MH - Zebrafish Proteins/genetics PMC - PMC6094114 OTO - NOTNLM OT - copper OT - cytochrome c oxidase OT - elesclomol OT - mitochondria COIS- Conflict of interest statement: S.S. and V.M.G. are listed as inventors on a provisional patent application filed by Texas A&M University. EDAT- 2018/07/25 06:00 MHDA- 2018/09/21 06:00 PMCR- 2018/07/23 CRDT- 2018/07/25 06:00 PHST- 2018/07/25 06:00 [pubmed] PHST- 2018/09/21 06:00 [medline] PHST- 2018/07/25 06:00 [entrez] PHST- 2018/07/23 00:00 [pmc-release] AID - 1806296115 [pii] AID - 201806296 [pii] AID - 10.1073/pnas.1806296115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Aug 7;115(32):8161-8166. doi: 10.1073/pnas.1806296115. Epub 2018 Jul 23.