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Human Molecular Genetics, 2001, Vol. 10, No. 11 1221-1228
© 2001 Oxford University Press

Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA

Vanna Geromel1, Noman Kadhom1, Irène Cebalos-Picot2, Olivier Ouari3, Ange Polidori3, Arnold Munnich1, Agnès Rötig1 and Pierre Rustin1,+

1Unité de Recherches sur les Handicaps Génétiques de l’Enfant (INSERM U393) and 2Unité de Recherches ‘Génétique, Chromosome et Cancer’ (INSERM U383), Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France and 3Laboratoire ‘Chimie Bioorganique et des Systèmes Vectoriels’, Université d’Avignon et de Pays du Vaucluse, Faculté de Science, 33 rue L. Pasteur, 84000 Avignon, France

The oxidative stress resulting from the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the mitochondrial ATPase 6 gene was investigated in cultured skin fibroblasts from two patients presenting an isolated complex V deficiency. Taken as an index for superoxide overproduction, a huge induction of the superoxide dismutase (SOD) activity was observed in these fibroblasts harboring >90% of mutant mitochondrial DNA. The oxidative stress denoted by the high SOD activity was associated with increased cell death. In glucose-rich medium, apoptosis appeared as the main cell death process associated with complex V deficiency. Complex V-deficient fibroblasts, which showed a high SOD induction and stained positive for all studied apoptosis markers, were successfully rescued by perfluoro-tris-phenyl nitrone, an antioxidant spin-trap molecule. This established that the superoxide production associated with the ATPase deficiency triggered by the NARP mutation could be sufficient to override cell antioxidant defenses and to result in cell commitment to die. The potential participation of superoxides and/or their derivatives in the pathogenic mechanism of specific respiratory chain disorders makes them a promising target for therapy.

+ To whom correspondence should be addressed. Tel: +33 1 44 38 15 84; Fax: +33 1 47 34 85 14; Email: rustin@necker.fr


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