The mitochondrial cytochrome c oxidase, the terminal enzyme of the respiratory chain, contains heme and copper centers for electron transfer. The conserved COX2 subunit contains the Cu(A) site, a binuclear copper center. The copper chaperones SCO1, SCO2, and COA6, are required for Cu(A) center formation. Loss of function of these chaperones and the concomitant cytochrome c oxidase deficiency cause severe human disorders. Here we analyzed the molecular function of COA6 and the consequences of COA6 deficiency for mitochondria. Our analyses show that loss of COA6 causes combined complex I and complex IV deficiency and impacts membrane potential-driven protein transport across the inner membrane. We demonstrate that COA6 acts as a thiol-reductase to reduce disulfide bridges of critical cysteine residues in SCO1 and SCO2. Cysteines within the CX(3)CX(N)H domain of SCO2 mediate its interaction with COA6 but are dispensable for SCO2-SCO1 interaction. Our analyses define COA6 as thiol-reductase, which is essential for Cu(A) biogenesis.
%0 Journal Article
%1 pacheu-grauCOA6FacilitatesCytochrome2020
%A Pacheu-Grau, David
%A Wasilewski, Michał
%A Oeljeklaus, Silke
%A Gibhardt, Christine Silvia
%A Aich, Abhishek
%A Chudenkova, Margarita
%A Dennerlein, Sven
%A Deckers, Markus
%A Bogeski, Ivan
%A Warscheid, Bettina
%A Chacinska, Agnieszka
%A Rehling, Peter
%C Netherlands
%D 2020
%J Journal of molecular biology
%K Carrier Cells,Humans,Metallochaperones,mitochondria,Mitochondria/genetics/*metabolism,Mitochondrial Chain Chaperones/genetics/*metabolism,Mutation,Protein Complex Compounds/*chemistry,to_read Proteins/genetics/*metabolism,COA6,copper Proteins/genetics/*metabolism,HEK293 Proteins/genetics/*metabolism,Molecular Transport Transport,Electron Transport,Sulfhydryl c center,cytochrome metallochaperones,Copper/*metabolism,Cu(A) oxidase,Electron
%N 7
%P 2067--2079
%R 10.1016/j.jmb.2020.01.036
%T COA6 Facilitates Cytochrome c Oxidase Biogenesis as Thiol-reductase for Copper Metallochaperones in Mitochondria.
%V 432
%X The mitochondrial cytochrome c oxidase, the terminal enzyme of the respiratory chain, contains heme and copper centers for electron transfer. The conserved COX2 subunit contains the Cu(A) site, a binuclear copper center. The copper chaperones SCO1, SCO2, and COA6, are required for Cu(A) center formation. Loss of function of these chaperones and the concomitant cytochrome c oxidase deficiency cause severe human disorders. Here we analyzed the molecular function of COA6 and the consequences of COA6 deficiency for mitochondria. Our analyses show that loss of COA6 causes combined complex I and complex IV deficiency and impacts membrane potential-driven protein transport across the inner membrane. We demonstrate that COA6 acts as a thiol-reductase to reduce disulfide bridges of critical cysteine residues in SCO1 and SCO2. Cysteines within the CX(3)CX(N)H domain of SCO2 mediate its interaction with COA6 but are dispensable for SCO2-SCO1 interaction. Our analyses define COA6 as thiol-reductase, which is essential for Cu(A) biogenesis.
@article{pacheu-grauCOA6FacilitatesCytochrome2020,
abstract = {The mitochondrial cytochrome c oxidase, the terminal enzyme of the respiratory chain, contains heme and copper centers for electron transfer. The conserved COX2 subunit contains the Cu(A) site, a binuclear copper center. The copper chaperones SCO1, SCO2, and COA6, are required for Cu(A) center formation. Loss of function of these chaperones and the concomitant cytochrome c oxidase deficiency cause severe human disorders. Here we analyzed the molecular function of COA6 and the consequences of COA6 deficiency for mitochondria. Our analyses show that loss of COA6 causes combined complex I and complex IV deficiency and impacts membrane potential-driven protein transport across the inner membrane. We demonstrate that COA6 acts as a thiol-reductase to reduce disulfide bridges of critical cysteine residues in SCO1 and SCO2. Cysteines within the CX(3)CX(N)H domain of SCO2 mediate its interaction with COA6 but are dispensable for SCO2-SCO1 interaction. Our analyses define COA6 as thiol-reductase, which is essential for Cu(A) biogenesis.},
added-at = {2024-05-17T13:01:35.000+0200},
address = {Netherlands},
author = {{Pacheu-Grau}, David and Wasilewski, Micha{\l} and Oeljeklaus, Silke and Gibhardt, Christine Silvia and Aich, Abhishek and Chudenkova, Margarita and Dennerlein, Sven and Deckers, Markus and Bogeski, Ivan and Warscheid, Bettina and Chacinska, Agnieszka and Rehling, Peter},
biburl = {https://www.bibsonomy.org/bibtex/2d01c9739d59c403c1739335952caed35/warscheidlab},
copyright = {Copyright {\copyright} 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.},
doi = {10.1016/j.jmb.2020.01.036},
interhash = {1e6b16a716be8e2c0a97192277a46c62},
intrahash = {d01c9739d59c403c1739335952caed35},
issn = {1089-8638 0022-2836},
journal = {Journal of molecular biology},
keywords = {Carrier Cells,Humans,Metallochaperones,mitochondria,Mitochondria/genetics/*metabolism,Mitochondrial Chain Chaperones/genetics/*metabolism,Mutation,Protein Complex Compounds/*chemistry,to_read Proteins/genetics/*metabolism,COA6,copper Proteins/genetics/*metabolism,HEK293 Proteins/genetics/*metabolism,Molecular Transport Transport,Electron Transport,Sulfhydryl c center,cytochrome metallochaperones,Copper/*metabolism,Cu(A) oxidase,Electron},
langid = {english},
month = mar,
number = 7,
pages = {2067--2079},
pmcid = {PMC7254062},
pmid = {32061935},
timestamp = {2024-05-17T13:01:35.000+0200},
title = {{{COA6 Facilitates Cytochrome}} c {{Oxidase Biogenesis}} as {{Thiol-reductase}} for {{Copper Metallochaperones}} in {{Mitochondria}}.},
volume = 432,
year = 2020
}