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Loss of iron homeostasis in Friedreich ataxia cells and impairment of the oxidative stress response

McGill University
Publication Date
  • Biology
  • Neuroscience.
  • Biology


Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin and characterized by a debilitating loss of coordination. In yeast, complete loss of frataxin causes mitochondrial iron accumulation and oxidative stress. Although FRDA cells exhibit impaired respiratory complex activity and greater sensitivity to hydrogen peroxide-induced apoptotic cell death, an increase in steady-state mitochondrial iron levels has not been conclusively shown. Pulse-chase experiments using FRDA fibroblasts suggest that severe disturbances in iron metabolism occur following supplementation with iron levels sufficient to overwhelm residual frataxin in these cells. Moreover, frataxin appears capable of forming high molecular weight complexes with iron in vitro, but the propensity of iron to nonspecifically associate with biomacromolecules complicates confirmation of this finding. Lastly, induction of oxidative stress in FRDA cells by iron loading appears unable to initiate the expected transcriptional upregulation of the antioxidant enzyme mitochondrial superoxide dismutase, possibly as a result of failed NF-kappaB activation.

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