title: The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis.
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.
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Christopher J
authors: CJ
authors: Hlynialuk
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Binbing
authors: B
authors: Ling
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Zakery N
authors: ZN
authors: Baker
authors: Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA.
authors: Paul A
authors: PA
authors: Cobine
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Lisa D
authors: LD
authors: Yu
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Aren
authors: A
authors: Boulet
authors: Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
authors: Timothy
authors: T
authors: Wai
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Amzad
authors: A
authors: Hossain
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; Faculty of Science, Damanhour University, Damanhour 22516, Egypt.
authors: Amr M
authors: AM
authors: El Zawily
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Pamela J
authors: PJ
authors: McFie
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Scot J
authors: SJ
authors: Stone
authors: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Francisca
authors: F
authors: Diaz
authors: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Carlos T
authors: CT
authors: Moraes
authors: Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
authors: Deepa
authors: D
authors: Viswanathan
authors: Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
authors: Michael J
authors: MJ
authors: Petris
authors: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. Electronic address: scot.leary@usask.ca.
authors: Scot C
authors: SC
authors: Leary