Frataxin deficiency enhances apoptosis in cells differentiating into neuroectoderm

Deficiency of the mitochondrial matrix protein frataxin causes Friedreich a taxia. Frataxin function is believed to be related to mitochondrial iron me tabolism and free radical production. In Friedreich ataxia, loss of dorsal root ganglia neurons occurs early in life, suggesting a developmental proce ss. In addition, frataxin knockout mice die during embryonic life, further suggesting that frataxin is necessary for normal development. In this study we examine the role of frataxin in neuronal differentiation by using the P 19 embryonic carcinoma cell line as a model system. We produced stably tran sfected clones with antisense or sense frataxin constructs. During retinoic acid-induced neurogenesis of frataxin-deficient cells there was a striking rise in cell death, while cell division remained unaffected. However, frat axin deficiency does not affect cell survival in cells induced to different iate into cardiomyocytes. Frataxin deficiency enhances apoptosis of retinoi c acid-stimulated cells, and the number of neuronal-like cells expressing M AP2 was dramatically reduced in these clones. In addition, we found that an tisense clones induced to differentiate into neuroectoderm with retinoic ac id have increased production of reactive oxygen species, and that only cell s noncommitted to the neuronal lineages could be rescued by the addition of the antioxidant N-acetyl-cysteine (NAC). However, NAC treatment had no eff ect in increasing the number of terminally differentiated neuronal-like cel ls in frataxin-deficient clones' Our results suggest that frataxin deficien cy may render cells susceptible to apoptosis after exposure to appropriate stimuli.