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

Alberto Casarin1, Gianpietro Giorgi1, Vanessa Pertegato1, Roberta Siviero2, Cristina Cerqua1, Mara Doimo1, Giuseppe Basso3, Sabrina Sacconi4, Matteo Cassina1, Rosario Rizzuto2, Sonja Brosel5, Mercy M Davidson5, Salvatore DiMauro5, Eric A Schon56, Maurizio Clementi1, Eva Trevisson1 and Leonardo Salviati1*

Author Affiliations

1 Clinical Genetics Unit, Dept. of Pediatrics, University of Padova, Via Giustiniani 3, Padova, 35128, Italy

2 Dept. of Biomedical Sciences, University of Padova, Padova, Italy

3 Hematology-Oncology Laboratory, Dept. of Pediatrics, University of Padova, Padova, Italy

4 Centre de référence des Maladies neuromusculaires and CNRS UMR6543, Nice University Hospital, Nice, France

5 Departments of Neurology, Columbia University, New York, NY, USA

6 Department of Genetics and Development, Columbia University, New York, NY, USA

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Orphanet Journal of Rare Diseases 2012, 7:21  doi:10.1186/1750-1172-7-21

Published: 19 April 2012



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.


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..


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.


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.

COX deficiency; Bezafibrate; SCO2; Copper chaperones; Copper supplementation