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Elesclomol Restores Mitochondrial Function in Genetic Models of Copper Deficiency

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Elesclomol Restores Mitochondrial Function in Genetic Models of Copper Deficiency Elesclomol restores mitochondrial function in genetic models of copper deficiency Shivatheja Somaa, Andrew J. Latimerb, Haarin Chunc, Alison C. Vicarya, Shrishiv A. Timbaliaa, Aren Bouletd, Jennifer J. Rahne, Sherine S. L. Chane, Scot C. Learyd, Byung-Eun Kimc, Jonathan D. Gitlinb, and Vishal M. Gohila,1 aDepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; bEugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA 02543; cDepartment of Animal and Avian Sciences, University of Maryland, College Park, MD 20742; dDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; and eDepartment of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425 Edited by Amy C. Rosenzweig, Northwestern University, Evanston, IL, and approved July 3, 2018 (received for review April 11, 2018) Copper is an essential cofactor of cytochrome c oxidase (CcO), the other proteins, Coa6 and Cox19, have also been shown to be part of terminal enzyme of the mitochondrial respiratory chain. Inherited this copper delivery pathway in the IMS (10–13). loss-of-function mutations in several genes encoding proteins re- In humans, inherited partial loss-of-function mutations in quired for copper delivery to CcO result in diminished CcO activity SCO1, SCO2, and COA6 result in a CcO deficiency and are as- and severe pathologic conditions in affected infants. Copper sup- sociated with hepatopathy, metabolic acidosis, cardiomyopathy, plementation restores CcO function in patient cells with mutations and neurological defects in affected patients (14–16). Copper in two of these genes, COA6 and SCO2, suggesting a potential supplementation rescues CcO deficiency in myoblasts from pa- therapeutic approach. However, direct copper supplementation tients with mutations in SCO2 (17) and restores CcO activity in has not been therapeutically effective in human patients, under- COA6-deficient yeast and human patient cell lines (16, 18), scoring the need to identify highly efficient copper transporting suggesting that efficient delivery of copper to mitochondria could pharmacological agents. By using a candidate-based approach, we restore CcO activity by bypassing SCO2 and COA6 functions. In an identified an investigational anticancer drug, elesclomol (ES), that attempt to translate these observations in a clinical setting, s.c. in- COA6 rescues respiratory defects of -deficient yeast cells by in- jections of copper histidine were administered to a patient with an creasing mitochondrial copper content and restoring CcO activity. SCO2 mutation. Although copper supplementation improved the ES also rescues respiratory defects in other yeast mutants of cop- patient’s hypertrophic cardiomyopathy, it did not improve other per metabolism, suggesting a broader applicability. Low nanomo- clinical outcomes or survival (19). Thus, a more effective mecha- lar concentrations of ES reinstate copper-containing subunits of nism for restoration of copper homeostasis will be required for CcO in a zebrafish model of copper deficiency and in a series of human therapeutic agents. The present study employed yeast copper-deficient mammalian cells, including those derived from a coa6Δ cells to identify compounds that can efficiently transport patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function copper across biological membranes and restore mitochondrial of missing transporters and chaperones of copper, and may have respiratory chain function over a broad range of concentrations. potential in treating human disorders of copper metabolism. This approach identified elesclomol (ES), which was shown to copper | mitochondria | elesclomol | cytochrome c oxidase Significance opper is an essential micronutrient required for the assembly Inherited pathogenic mutations in genes required for copper Cand activity of cytochrome c oxidase (CcO), the terminal delivery to cytochrome c oxidase (CcO) perturb mitochondrial enzyme of the mitochondrial respiratory chain that catalyzes the energy metabolism and result in fatal mitochondrial disease. A reduction of molecular oxygen and drives mitochondrial energy prior attempt to treat human patients with these mutations by direct copper supplementation was not successful, possibly production (1, 2). CcO is a highly conserved, multimeric inner because of inefficient copper delivery to the mitochondria. We mitochondrial membrane protein complex that has two copper- performed a targeted search to identify compounds that can containing subunits, Cox1 and Cox2, which together form its efficiently transport copper across biological membranes and catalytic core (2). Copper delivery to mitochondria and its in- identified elesclomol (ES), an investigational anticancer drug, sertion into these copper-containing subunits is an intricate as the most efficient copper delivery agent. ES rescues CcO process that requires multiple metallochaperones and ancillary function in yeast, zebrafish, and mammalian models of copper BIOCHEMISTRY proteins (3). Failure to deliver copper to Cox1 and Cox2 disrupts deficiency by increasing cellular and mitochondrial copper con- CcO assembly and results in a respiratory deficiency. tent. Thus, our study offers a possibility of repurposing this anti- Cytosolic copper is delivered to the mitochondrial matrix via cancer drug for the treatment of disorders of copper metabolism. the recently identified yeast protein Pic2 (4), where it is stored in a ligand-bound form (5). This mitochondrial matrix copper pool Author contributions: S.S. and V.M.G. designed research; S.S., A.J.L., H.C., A.C.V., S.A.T., A.B., and J.J.R. performed research; A.J.L., H.C., A.B., J.J.R., S.S.L.C., S.C.L., B.-E.K., and is the main source of copper ions that are inserted into the CcO J.D.G. contributed new reagents/analytic tools; S.S., A.J.L., H.C., A.C.V., S.A.T., J.J.R., subunits in the mitochondrial intermembrane space (IMS) (6). Mo- S.S.L.C., S.C.L., B.-E.K., J.D.G., and V.M.G. analyzed data; and S.S., S.C.L., J.D.G., and bilization of copper from the mitochondrial matrix to the IMS for its V.M.G. wrote the paper. delivery to copper sites in CcO subunits requires a number of evo- 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. lutionarily conserved proteins (3). The precise molecular functions of This article is a PNAS Direct Submission. these proteins have remained unsolved, except for the metal- This open access article is distributed under Creative Commons Attribution-NonCommercial- lochaperones Cox17, Sco1, Sco2, and Cox11, which have been shown NoDerivatives License 4.0 (CC BY-NC-ND). to transfer copper to CcO subunits in a bucket-brigade fashion (3). 1To whom correspondence should be addressed. Email: [email protected]. Specifically, Cox17 receives copper from the mitochondrial matrix This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and transfers it to Cox11 and Sco1/Sco2 (7), which then metallate 1073/pnas.1806296115/-/DCSupplemental. copper sites on Cox1 and Cox2, respectively (8, 9). Recently, two Published online July 23, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1806296115 PNAS | August 7, 2018 | vol. 115 | no. 32 | 8161–8166 Downloaded by guest on September 28, 2021 reestablish subcellular copper homeostasis in copper-deficient cells supplemented with ES (Fig. 1G). ES supplementation also cells, highlighting its therapeutic potential for human diseases of moderately increased total cellular copper levels (Fig. 1H). To copper metabolism. further corroborate that ES increases mitochondrial copper levels by actively transporting extracellular copper into the cells, Results we decreased copper availability in the extracellular compart- A Targeted Search for Copper-Binding Agents Identifies ES as the ment by cotreatment with ES and a known copper chelator, Most Potent Pharmacological Agent in Rescuing Respiratory Defects bathocuproine disulfonate (BCS). As expected, BCS treatment of Yeast coa6Δ Cells. We tested a number of copper-binding resulted in reduced respiratory growth of WT cells, which was pharmacological agents (20) for their ability to rescue respiratory rescued by cotreatment with ES, suggesting that ES is also able deficient growth of coa6Δ cells. Among all of the compounds to overcome pharmacological copper deficiency by outcompeting tested, ES was unique in that it rescued respiratory growth at low BCS (SI Appendix,Fig.S4A). Moreover, ES-mediated rescue of nanomolar concentrations without exhibiting overt toxicity over coa6Δ was diminished in the presence of BCS (SI Appendix,Fig. a broad range of concentrations (SI Appendix, Fig. S1). ES res- S4B). To determine whether ES is able to bypass a mitochondrial cued the respiratory growth of coa6Δ cells with an ED50 of copper transporter, Pic2, we performed ES supplementation in 0.8 nM (SI Appendix, Fig. S2). ES-mediated growth rescue of pic2Δ and coa6Δpic2Δ cells. Although, under the conditions tested, coa6Δ cells was also observed on solid growth medium contain- we did not observe a respiratory growth defect of pic2Δ cells, ES did ing a nonfermentable carbon source (Fig. 1A). Consistent with rescue coa6Δpic2Δ cells, suggesting that this compound can deliver the rescue of respiratory growth, ES supplementation restored copper to the mitochondria independent
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