Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates. We show that the pathogenic mutation in COA6 does not affect its import into mitochondria but impairs its maturation and stability. Furthermore, we show that COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1. Our data reveal that COA6 is intricately involved in the copper-dependent biogenesis of COX2.
%0 Journal Article
%1 stroudCOA6MitochondrialComplex2015
%A Stroud, David A.
%A Maher, Megan J.
%A Lindau, Caroline
%A Vögtle, F.-Nora
%A Frazier, Ann E.
%A Surgenor, Elliot
%A Mountford, Hayley
%A Singh, Abeer P.
%A Bonas, Matteo
%A Oeljeklaus, Silke
%A Warscheid, Bettina
%A Meisinger, Chris
%A Thorburn, David R.
%A Ryan, Michael T.
%C England
%D 2015
%J Human molecular genetics
%K Cardiomyopathies/*genetics,Carrier Cells,Humans,Infant,Male,Membrane Chaperones,to_read Complex IV/*genetics/metabolism,Fibroblasts/cytology/enzymology,HEK293 Proteins/*genetics/metabolism,Copper/metabolism,Electron Proteins/*genetics/metabolism,Molecular Proteins/*metabolism,Mitochondrial Transport
%N 19
%P 5404--5415
%R 10.1093/hmg/ddv265
%T COA6 Is a Mitochondrial Complex IV Assembly Factor Critical for Biogenesis of mtDNA-encoded COX2.
%V 24
%X Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates. We show that the pathogenic mutation in COA6 does not affect its import into mitochondria but impairs its maturation and stability. Furthermore, we show that COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1. Our data reveal that COA6 is intricately involved in the copper-dependent biogenesis of COX2.
@article{stroudCOA6MitochondrialComplex2015,
abstract = {Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates. We show that the pathogenic mutation in COA6 does not affect its import into mitochondria but impairs its maturation and stability. Furthermore, we show that COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1. Our data reveal that COA6 is intricately involved in the copper-dependent biogenesis of COX2.},
added-at = {2024-05-17T13:01:35.000+0200},
address = {England},
author = {Stroud, David A. and Maher, Megan J. and Lindau, Caroline and V{\"o}gtle, F.-Nora and Frazier, Ann E. and Surgenor, Elliot and Mountford, Hayley and Singh, Abeer P. and Bonas, Matteo and Oeljeklaus, Silke and Warscheid, Bettina and Meisinger, Chris and Thorburn, David R. and Ryan, Michael T.},
biburl = {https://www.bibsonomy.org/bibtex/2c121a3191e7c7d8841efe351d4003445/warscheidlab},
copyright = {{\copyright} The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.},
doi = {10.1093/hmg/ddv265},
interhash = {addd942f85f9c995fcd823ee0a6338a3},
intrahash = {c121a3191e7c7d8841efe351d4003445},
issn = {1460-2083 0964-6906},
journal = {Human molecular genetics},
keywords = {Cardiomyopathies/*genetics,Carrier Cells,Humans,Infant,Male,Membrane Chaperones,to_read Complex IV/*genetics/metabolism,Fibroblasts/cytology/enzymology,HEK293 Proteins/*genetics/metabolism,Copper/metabolism,Electron Proteins/*genetics/metabolism,Molecular Proteins/*metabolism,Mitochondrial Transport},
langid = {english},
month = oct,
number = 19,
pages = {5404--5415},
pmid = {26160915},
timestamp = {2024-05-17T13:01:35.000+0200},
title = {{{COA6}} Is a Mitochondrial Complex {{IV}} Assembly Factor Critical for Biogenesis of {{mtDNA-encoded COX2}}.},
volume = 24,
year = 2015
}