Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells

Emmanuel P Dassa; Eric Dufour; Sérgio Gonçalves; Vincent Paupe; Gertjan A J Hakkaart; Howard T Jacobs; Pierre Rustin

doi:10.1002/emmm.200900001

Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells

EMBO Mol Med. 2009 Apr;1(1):30-6. doi: 10.1002/emmm.200900001.

Authors

Emmanuel P Dassa¹, Eric Dufour, Sérgio Gonçalves, Vincent Paupe, Gertjan A J Hakkaart, Howard T Jacobs, Pierre Rustin

Affiliation

¹ Inserm, U676 and Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkyl and Aryl Transferases / deficiency
Alkyl and Aryl Transferases / metabolism
Animals
Antimycin A / analogs & derivatives
Antimycin A / pharmacology
Cell Line, Transformed
Cell Survival / drug effects
Ciona intestinalis / enzymology
Cytochrome-c Oxidase Deficiency / enzymology*
Cytochrome-c Oxidase Deficiency / pathology*
Electron Transport / drug effects
Electron Transport Complex IV
Fibroblasts / drug effects
Fibroblasts / enzymology
Gene Knockdown Techniques
Genetic Complementation Test*
Humans
Hydrogen Peroxide / pharmacology
Membrane Proteins / deficiency
Membrane Proteins / metabolism
Mitochondrial Proteins
Mutation / genetics
Oxidative Stress / drug effects
Oxidoreductases / metabolism*
Plant Proteins
Skin / pathology

Substances

Membrane Proteins
Mitochondrial Proteins
Plant Proteins
antimycin
Antimycin A
Hydrogen Peroxide
Oxidoreductases
alternative oxidase
COX10 protein, human
Electron Transport Complex IV
Alkyl and Aryl Transferases