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Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals

The redox activity of cytochrome c oxidase (COX), the terminal oxidase of the mitochondrial respiratory chain (MRC), depends on the incorporation of iron and copper into its catalytic centers. Many mitochondrial proteins have specific roles for the synthesis and delivery of metal-containing cofactor...

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Autores principales: Brischigliaro, Michele, Badocco, Denis, Costa, Rodolfo, Viscomi, Carlo, Zeviani, Massimo, Pastore, Paolo, Fernández-Vizarra, Erika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160823/
https://www.ncbi.nlm.nih.gov/pubmed/35663391
http://dx.doi.org/10.3389/fcell.2022.892069
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author Brischigliaro, Michele
Badocco, Denis
Costa, Rodolfo
Viscomi, Carlo
Zeviani, Massimo
Pastore, Paolo
Fernández-Vizarra, Erika
author_facet Brischigliaro, Michele
Badocco, Denis
Costa, Rodolfo
Viscomi, Carlo
Zeviani, Massimo
Pastore, Paolo
Fernández-Vizarra, Erika
author_sort Brischigliaro, Michele
collection PubMed
description The redox activity of cytochrome c oxidase (COX), the terminal oxidase of the mitochondrial respiratory chain (MRC), depends on the incorporation of iron and copper into its catalytic centers. Many mitochondrial proteins have specific roles for the synthesis and delivery of metal-containing cofactors during COX biogenesis. In addition, a large set of different factors possess other molecular functions as chaperones or translocators that are also necessary for the correct maturation of these complexes. Pathological variants in genes encoding structural MRC subunits and these different assembly factors produce respiratory chain deficiency and lead to mitochondrial disease. COX deficiency in Drosophila melanogaster, induced by downregulated expression of three different assembly factors and one structural subunit, resulted in decreased copper content in the mitochondria accompanied by different degrees of increase in the cytosol. The disturbances in metal homeostasis were not limited only to copper, as some changes in the levels of cytosolic and/or mitochondrial iron, manganase and, especially, zinc were observed in several of the COX-deficient groups. The altered copper and zinc handling in the COX defective models resulted in a transcriptional response decreasing the expression of copper transporters and increasing the expression of metallothioneins. We conclude that COX deficiency is generally responsible for an altered mitochondrial and cellular homeostasis of transition metals, with variations depending on the origin of COX assembly defect.
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spelling pubmed-91608232022-06-03 Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals Brischigliaro, Michele Badocco, Denis Costa, Rodolfo Viscomi, Carlo Zeviani, Massimo Pastore, Paolo Fernández-Vizarra, Erika Front Cell Dev Biol Cell and Developmental Biology The redox activity of cytochrome c oxidase (COX), the terminal oxidase of the mitochondrial respiratory chain (MRC), depends on the incorporation of iron and copper into its catalytic centers. Many mitochondrial proteins have specific roles for the synthesis and delivery of metal-containing cofactors during COX biogenesis. In addition, a large set of different factors possess other molecular functions as chaperones or translocators that are also necessary for the correct maturation of these complexes. Pathological variants in genes encoding structural MRC subunits and these different assembly factors produce respiratory chain deficiency and lead to mitochondrial disease. COX deficiency in Drosophila melanogaster, induced by downregulated expression of three different assembly factors and one structural subunit, resulted in decreased copper content in the mitochondria accompanied by different degrees of increase in the cytosol. The disturbances in metal homeostasis were not limited only to copper, as some changes in the levels of cytosolic and/or mitochondrial iron, manganase and, especially, zinc were observed in several of the COX-deficient groups. The altered copper and zinc handling in the COX defective models resulted in a transcriptional response decreasing the expression of copper transporters and increasing the expression of metallothioneins. We conclude that COX deficiency is generally responsible for an altered mitochondrial and cellular homeostasis of transition metals, with variations depending on the origin of COX assembly defect. Frontiers Media S.A. 2022-05-19 /pmc/articles/PMC9160823/ /pubmed/35663391 http://dx.doi.org/10.3389/fcell.2022.892069 Text en Copyright © 2022 Brischigliaro, Badocco, Costa, Viscomi, Zeviani, Pastore and Fernández-Vizarra. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Brischigliaro, Michele
Badocco, Denis
Costa, Rodolfo
Viscomi, Carlo
Zeviani, Massimo
Pastore, Paolo
Fernández-Vizarra, Erika
Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals
title Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals
title_full Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals
title_fullStr Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals
title_full_unstemmed Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals
title_short Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals
title_sort mitochondrial cytochrome c oxidase defects alter cellular homeostasis of transition metals
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160823/
https://www.ncbi.nlm.nih.gov/pubmed/35663391
http://dx.doi.org/10.3389/fcell.2022.892069
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