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PMID:23345593

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Citation

Leary, SC, Cobine, PA, Nishimura, T, Verdijk, RM, de Krijger, R, de Coo, R, Tarnopolsky, MA, Winge, DR and Shoubridge, EA (2013) COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux. Mol. Biol. Cell 24:683-91

Abstract

SCO1 and SCO2 are metallochaperones whose principal function is to add two copper ions to the catalytic core of cytochrome c oxidase (COX). However, affected tissues of SCO1 and SCO2 patients exhibit a combined deficiency in COX activity and total copper content, suggesting additional roles for these proteins in the regulation of cellular copper homeostasis. Here we show that both the redox state of the copper-binding cysteines of SCO1 and the abundance of SCO2 correlate with cellular copper content and that these relationships are perturbed by mutations in SCO1 or SCO2, producing a state of apparent copper overload. The copper deficiency in SCO patient fibroblasts is rescued by knockdown of ATP7A, a trans-Golgi, copper-transporting ATPase that traffics to the plasma membrane during copper overload to promote efflux. To investigate how a signal from SCO1 could be relayed to ATP7A, we examined the abundance and subcellular distribution of several soluble COX assembly factors. We found that COX19 partitions between mitochondria and the cytosol in a copper-dependent manner and that its knockdown partially rescues the copper deficiency in patient cells. These results demonstrate that COX19 is necessary for the transduction of a SCO1-dependent mitochondrial redox signal that regulates ATP7A-mediated cellular copper efflux.

Links

PubMed PMC3596241 Online version:10.1091/mbc.E12-09-0705

Keywords

Adenosine Triphosphatases/genetics; Adenosine Triphosphatases/metabolism; Carrier Proteins/metabolism; Cation Transport Proteins/genetics; Cation Transport Proteins/metabolism; Cell Line; Cell Membrane/metabolism; Copper/metabolism; Fibroblasts; Humans; Ion Transport; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mitochondria/genetics; Mitochondria/metabolism; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; Oxidation-Reduction; RNA Interference; RNA, Small Interfering; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:COX19

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:COX19

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:COX19

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CRYNB:COX19

GO:0031930: mitochondria-nucleus signaling pathway

ECO:0000315:

P

COX19 is a required for the transduction of a SCO-dependent redox signal from mitochondria to ATP7A.

Figure 5A-C shows the knockdown of COX19 and PET191. Knockdown of COX19 reduces cellular copper levels when compared to parental lines, whereas PET191 knockdown does not affect copper levels. COX19 is critical for regulating cellular copper efflux.

complete
CACAO 9684

HUMAN:COX19

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:COX19

part_of

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:COX19

involved_in

GO:0006878: cellular copper ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:COX19

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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