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Open Access 01-12-2012 | Research

Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations

Authors: Alberto Casarin, Gianpietro Giorgi, Vanessa Pertegato, Roberta Siviero, Cristina Cerqua, Mara Doimo, Giuseppe Basso, Sabrina Sacconi, Matteo Cassina, Rosario Rizzuto, Sonja Brosel, Mercy M Davidson, Salvatore DiMauro, Eric A Schon, Maurizio Clementi, Eva Trevisson, Leonardo Salviati

Published in: Orphanet Journal of Rare Diseases | Issue 1/2012

Abstract

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 CuCl₂ 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.

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Title: Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations
Authors: Alberto Casarin
Gianpietro Giorgi
Vanessa Pertegato
Roberta Siviero
Cristina Cerqua
Mara Doimo
Giuseppe Basso
Sabrina Sacconi
Matteo Cassina
Rosario Rizzuto
Sonja Brosel
Mercy M Davidson
Salvatore DiMauro
Eric A Schon
Maurizio Clementi
Eva Trevisson
Leonardo Salviati
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2012
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/1750-1172-7-21

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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