title: Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations.
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.
authors.affiliation: Clinical Genetics Unit, Dept of Pediatrics, University of Padova, Via Giustiniani 3, Padova 35128, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Casarin
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Giorgi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pertegato
authors.forename: Roberta
authors.initials: R
authors.lastname: Siviero
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerqua
authors.forename: Mara
authors.initials: M
authors.lastname: Doimo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.forename: Matteo
authors.initials: M
authors.lastname: Cassina
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Sonja
authors.initials: S
authors.lastname: Brosel
authors.forename: Mercy
authors.initials: M
authors.lastname: M Davidson
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimauro
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.forename: Maurizio
authors.initials: M
authors.lastname: Clementi
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001629:Bezafibrate / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003300:Copper / Q000494:pharmacology*; D030401:Cytochrome-c Oxidase Deficiency / Q000188:drug therapy / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018832:Molecular Chaperones; D009154:Mutation
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C400285:SCO2 protein, human; D003300:Copper; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D001629:Bezafibrate