The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis
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...
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2015-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715000327 |
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doaj-0340b7e99d004b629b58872104cbc6a22020-11-25T01:30:55ZengElsevierCell Reports2211-12472015-02-0110693394310.1016/j.celrep.2015.01.019The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper HomeostasisChristopher J. Hlynialuk0Binbing Ling1Zakery N. Baker2Paul A. Cobine3Lisa D. Yu4Aren Boulet5Timothy Wai6Amzad Hossain7Amr M. El Zawily8Pamela J. McFie9Scot J. Stone10Francisca Diaz11Carlos T. Moraes12Deepa Viswanathan13Michael J. Petris14Scot C. Leary15Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biological Sciences, Auburn University, Auburn, AL 36849, USADepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaInstitute for Genetics, University of Cologne, 50931 Cologne, GermanyDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Biochemistry, University of Missouri, Columbia, MO 65211, USADepartment of Biochemistry, University of Missouri, Columbia, MO 65211, USADepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaHuman 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.http://www.sciencedirect.com/science/article/pii/S2211124715000327 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Christopher J. Hlynialuk Binbing Ling Zakery N. Baker Paul A. Cobine Lisa D. Yu Aren Boulet Timothy Wai Amzad Hossain Amr M. El Zawily Pamela J. McFie Scot J. Stone Francisca Diaz Carlos T. Moraes Deepa Viswanathan Michael J. Petris Scot C. Leary |
| spellingShingle |
Christopher J. Hlynialuk Binbing Ling Zakery N. Baker Paul A. Cobine Lisa D. Yu Aren Boulet Timothy Wai Amzad Hossain Amr M. El Zawily Pamela J. McFie Scot J. Stone Francisca Diaz Carlos T. Moraes Deepa Viswanathan Michael J. Petris Scot C. Leary The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis Cell Reports |
| author_facet |
Christopher J. Hlynialuk Binbing Ling Zakery N. Baker Paul A. Cobine Lisa D. Yu Aren Boulet Timothy Wai Amzad Hossain Amr M. El Zawily Pamela J. McFie Scot J. Stone Francisca Diaz Carlos T. Moraes Deepa Viswanathan Michael J. Petris Scot C. Leary |
| author_sort |
Christopher J. Hlynialuk |
| title |
The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis |
| title_short |
The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis |
| title_full |
The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis |
| title_fullStr |
The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis |
| title_full_unstemmed |
The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis |
| title_sort |
mitochondrial metallochaperone sco1 is required to sustain expression of the high-affinity copper transporter ctr1 and preserve copper homeostasis |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2015-02-01 |
| description |
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. |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124715000327 |
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