title: Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells.
abstract: Cytochrome c oxidase (COX) deficiency is associated with a wide spectrum of clinical conditions, ranging from early onset devastating encephalomyopathy and cardiomyopathy, to neurological diseases in adulthood and in the elderly. No method of compensating successfully for COX deficiency has been reported so far. In vitro, COX-deficient human cells require additional glucose, pyruvate and uridine for normal growth and are specifically sensitive to oxidative stress. Here, we have tested whether the expression of a mitochondrially targeted, cyanide-resistant, alternative oxidase (AOX) from Ciona intestinalis could alleviate the metabolic abnormalities of COX-deficient human cells either from a patient harbouring a COX15 pathological mutation or rendered deficient by silencing the COX10 gene using shRNA. We demonstrate that the expression of the AOX, well-tolerated by the cells, compensates for both the growth defect and the pronounced oxidant-sensitivity of COX-deficient human cells.
authors.affiliation: Inserm, U676 and Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Emmanuel P
authors.initials: EP
authors.lastname: Dassa
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
authors.forename: Sérgio
authors.initials: S
authors.lastname: Gonçalves
authors.forename: Vincent
authors.initials: V
authors.lastname: Paupe
authors.forename: Gertjan A J
authors.initials: GA
authors.lastname: Hakkaart
authors.forename: Howard T
authors.initials: HT
authors.lastname: Jacobs
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002938:Ciona intestinalis / Q000201:enzymology; D030401:Cytochrome-c Oxidase Deficiency / Q000201:enzymology* / Q000473:pathology*; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D055785:Gene Knockdown Techniques; D005816:Genetic Complementation Test; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D010940:Plant Proteins; D012867:Skin / Q000473:pathology; D000099188:Alternative Oxidase
chemical_list: D019883:Alkyl and Aryl Transferases; D000968:Antimycin A; D003576:Electron Transport Complex IV; D006861:Hydrogen Peroxide; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D000099188:Alternative Oxidase; C032456:antimycin; C490115:COX10 protein, human