Abstract
BackgroundMutations 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.MethodsWe 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..ResultsIndividual 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.ConclusionsThese 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.
Highlights
Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy
BZF induces comparable increase of COX activity in different cell lines we focused on the effect on COX in different cell lines: HEK293 cells, primary skin fibroblasts from a healthy individual, and bone marrow-derived SEM cells
We detected similar increases of COX activity (+37%, +38%, and +43%) in the three cell types compared to BZF stimulates COX activity in SCO2 cells in a dose-dependent but peaks at 400 μM We analysed the effect of BZF in normal and COXdeficient fibroblasts
Summary
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. Mutations in COX assembly genes (mainly SURF1, SCO2, and COX10) are the most common cause of isolated COX deficiency [3]. These disorders are characterized by severe encephalomyopathy, and involvement of other tissues (hypertrophic cardiomyopathy in SCO2 patients[4], tubulopathy and/or cardiomyopathy in COX10 patients[5]), and usually leads to death in infancy or early childhood. SCO2 itself is a copper-binding protein, and it has been shown that copper supplementation can rescue COX deficiency in cells harboring mutations in this gene [9,10]. A preliminary trial in patients yielded promising results [11], and supplementation with copper salts is currently employed in patients with Menkes disease [12], the potential toxicity of these compounds is a major hindrance to their therapeutic use
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