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Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations
BACKGROUND: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic age...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445839/ https://www.ncbi.nlm.nih.gov/pubmed/22515166 http://dx.doi.org/10.1186/1750-1172-7-21 |
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author | Casarin, Alberto Giorgi, Gianpietro Pertegato, Vanessa Siviero, Roberta Cerqua, Cristina Doimo, Mara Basso, Giuseppe Sacconi, Sabrina Cassina, Matteo Rizzuto, Rosario Brosel, Sonja M Davidson, Mercy DiMauro, Salvatore Schon, Eric A Clementi, Maurizio Trevisson, Eva Salviati, Leonardo |
author_facet | Casarin, Alberto Giorgi, Gianpietro Pertegato, Vanessa Siviero, Roberta Cerqua, Cristina Doimo, Mara Basso, Giuseppe Sacconi, Sabrina Cassina, Matteo Rizzuto, Rosario Brosel, Sonja M Davidson, Mercy DiMauro, Salvatore Schon, Eric A Clementi, Maurizio Trevisson, Eva Salviati, Leonardo |
author_sort | Casarin, Alberto |
collection | PubMed |
description | BACKGROUND: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. METHODS: We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. RESULTS: Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl(2) and 200 μM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. CONCLUSIONS: These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined. |
format | Online Article Text |
id | pubmed-3445839 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-34458392012-09-20 Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations Casarin, Alberto Giorgi, Gianpietro Pertegato, Vanessa Siviero, Roberta Cerqua, Cristina Doimo, Mara Basso, Giuseppe Sacconi, Sabrina Cassina, Matteo Rizzuto, Rosario Brosel, Sonja M Davidson, Mercy DiMauro, Salvatore Schon, Eric A Clementi, Maurizio Trevisson, Eva Salviati, Leonardo Orphanet J Rare Dis Research BACKGROUND: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. METHODS: We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. RESULTS: Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl(2) and 200 μM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. CONCLUSIONS: These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined. BioMed Central 2012-04-19 /pmc/articles/PMC3445839/ /pubmed/22515166 http://dx.doi.org/10.1186/1750-1172-7-21 Text en Copyright ©2012 Casarin et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Casarin, Alberto Giorgi, Gianpietro Pertegato, Vanessa Siviero, Roberta Cerqua, Cristina Doimo, Mara Basso, Giuseppe Sacconi, Sabrina Cassina, Matteo Rizzuto, Rosario Brosel, Sonja M Davidson, Mercy DiMauro, Salvatore Schon, Eric A Clementi, Maurizio Trevisson, Eva Salviati, Leonardo Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
title | Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
title_full | Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
title_fullStr | Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
title_full_unstemmed | Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
title_short | Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
title_sort | copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445839/ https://www.ncbi.nlm.nih.gov/pubmed/22515166 http://dx.doi.org/10.1186/1750-1172-7-21 |
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