The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis

Christopher J. Hlynialuk, Binbing Ling, Zakery N. Baker, Paul A. Cobine, Lisa D. Yu, Aren Boulet, Timothy Wai, Amzad Hossain, Amr M. ElZawily, Pamela J. McFie, Scot J. Stone, Francisca Diaz, Carlos T. Moraes, Deepa Viswanathan, Michael J. Petris, Scot C. Leary

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Human SCO1 fulfills essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper (Cu) homeostasis, yet it remains unclear why pathogenic mutations in this gene cause such clinically heterogeneous forms of disease. Here, we establish a Sco1 mouse model of human disease and show that ablation of Sco1 expression in the liver is lethal owing to severe COX and Cu deficiencies. We further demonstrate that the Cu deficiency is explained by a functional connection between SCO1 and CTR1, the high-affinity transporter that imports Cu into the cell. CTR1 is rapidly degraded in the absence of SCO1 protein, and we show that its levels are restored in Sco1-/- mouse embryonic fibroblasts upon inhibition of the proteasome. These data suggest that mitochondrial signaling through SCO1 provides a post-translational mechanism to regulate CTR1-dependent Cu import into the cell, and they further underpin the importance of mitochondria in cellular Cu homeostasis.

Original languageEnglish (US)
Pages (from-to)933-943
Number of pages11
JournalCell reports
Volume10
Issue number6
DOIs
StatePublished - Feb 17 2015

Bibliographical note

Funding Information:
We wish to acknowledge Drs. Joe Prohaska (University of Minnesota Medical School), Dennis Winge (University of Utah), Dennis Thiele (Duke University), Jonathan Gitlin (Marine Biological Laboratory), and Jaekwon Lee (University of Nebraska-Lincoln) for helpful discussions; Drs. Dennis Thiele, Joe Prohaska, and Jack Kaplan (University of Chicago) for CTR1 or CCS1 antiserum; and Dr. Eric Shoubridge (McGill University) for Lrrprc liver samples. Grants-in-aid of research to S.C.L. from the Saskatchewan Health Research Foundation, the Canadian Institutes for Health Research (CIHR), and the Canadian Gene Cure Foundation, and to P.A.C. from the National Science Foundation funded this research. S.C.L. is a New Investigator of the CIHR, and T.W. is a long-term fellow of the Human Frontiers Science Program.

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