The Human Cytochrome c Oxidase Assembly Factors SCO1 and SCO2 Have Regulatory Roles in the Maintenance of Cellular Copper Homeostasis
Copyright policy )The Human Cytochrome c Oxidase Assembly Factors SCO1 and SCO2 Have Regulatory Roles in the Maintenance of Cellular Copper Homeostasis
Human SCO1 and SCO2 are metallochaperones that are essential for the assembly of the catalytic core of cytochrome c oxidase (COX). Here we show that they have additional, unexpected roles in cellular copper homeostasis. Mutations in either SCO result in a cellular copper deficiency that is both tissue and allele specific. This phenotype can be dissociated from the defects in COX assembly and is suppressed by overexpression of SCO2, but not SCO1. Overexpression of a SCO1 mutant in control cells in which wild-type SCO1 levels were reduced by shRNA recapitulates the copper-deficiency phenotype in SCO1 patient cells. The copper-deficiency phenotype reflects not a change in high-affinity copper uptake but rather a proportional increase in copper efflux. These results suggest a mitochondrial pathway for the regulation of cellular copper content that involves signaling through SCO1 and SCO2, perhaps by their thiol redox or metal-binding state.
- University of Utah United States
- McGill University Canada
- Huntsman Cancer Institute United States
- Montreal Neurological Institute and Hospital Canada
- University of Paris France
Physiology, HUMDISEASE, Electron Transport Complex IV, Mitochondrial Proteins, Mitochondrial Encephalomyopathies, Homeostasis, Humans, Molecular Biology, Cation Transport Proteins, Alleles, Cells, Cultured, Copper Transporter 1, Membrane Proteins, Cell Biology, Fibroblasts, Mitochondria, Phenotype, Organ Specificity, Mutation, Carrier Proteins, Copper, Molecular Chaperones, Signal Transduction
Physiology, HUMDISEASE, Electron Transport Complex IV, Mitochondrial Proteins, Mitochondrial Encephalomyopathies, Homeostasis, Humans, Molecular Biology, Cation Transport Proteins, Alleles, Cells, Cultured, Copper Transporter 1, Membrane Proteins, Cell Biology, Fibroblasts, Mitochondria, Phenotype, Organ Specificity, Mutation, Carrier Proteins, Copper, Molecular Chaperones, Signal Transduction
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