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

The oxidative stress resulting from the neurogenic ataxia retinitis pigment osa (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 induc tion of the superoxide dismutase (SOD) activity was observed in these fibro blasts harboring > 90% of mutant mitochondrial DNA, The oxidative stress de noted by the high SOD activity was associated with increased cell death. In glucose-rich medium, apoptosis appeared as the main cell death process ass ociated with complex V deficiency. Complex V-deficient fibroblasts, which s howed a high SOD induction and stained positive for all studied apoptosis m arkers, were successfully rescued by perfluoro-tris-phenyl nitrone, an anti oxidant 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 disor ders makes them a promising target for therapy.