Friedreich ataxia: the oxidative stress paradox

Hum Mol Genet. 2005 Feb 15;14(4):463-74. doi: 10.1093/hmg/ddi042. Epub 2004 Dec 22.


Friedreich ataxia (FRDA) results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur protein activity initially ascribed to mitochondrial iron overload. Recent in vitro data suggest that frataxin is necessary for iron incorporation in Fe-S cluster (ISC) and heme biosynthesis. In addition, several reports suggest that continuous oxidative damage resulting from hampered superoxide dismutases (SODs) signaling participates in the mitochondrial deficiency and ultimately the neuronal and cardiac cell death. This has led to the use of antioxidants such as idebenone for FRDA therapy. To further discern the role of oxidative stress in FRDA pathophysiology, we have tested the potential effect of increased antioxidant defense using an MnSOD mimetic (MnTBAP) and Cu,ZnSOD overexpression on the murine FRDA cardiomyopathy. Surprisingly, no positive effect was observed, suggesting that increased superoxide production could not explain by itself the FRDA cardiac pathophysiology. Moreover, we demonstrate that complete frataxin-deficiency neither induces oxidative stress in neuronal tissues nor alters the MnSOD expression and induction in the early step of the pathology (neuronal and cardiac) as previously suggested. We show that cytosolic ISC aconitase activity of iron regulatory protein-1 progressively decreases, whereas its apo-RNA binding form increases despite the absence of oxidative stress, suggesting that in a mammalian system the mitochondrial ISC assembly machinery is essential for cytosolic ISC biogenesis. In conclusion, our data demonstrate that in FRDA, mitochondrial iron accumulation does not induce oxidative stress and we propose that, contrary to the general assumption, FRDA is a neurodegenerative disease not associated with oxidative damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cytosol / enzymology
  • Free Radical Scavengers / metabolism
  • Friedreich Ataxia / metabolism*
  • Friedreich Ataxia / pathology
  • Gene Expression Profiling
  • Iron / metabolism
  • Iron Regulatory Protein 1 / metabolism*
  • Iron-Sulfur Proteins / metabolism
  • Manganese / metabolism
  • Metalloporphyrins / metabolism*
  • Mice
  • Mice, Knockout
  • Microarray Analysis
  • Mitochondria / physiology*
  • Neurons
  • Oxidation-Reduction
  • Oxidative Stress*
  • RNA / metabolism
  • Superoxide Dismutase / metabolism*


  • Free Radical Scavengers
  • Iron-Sulfur Proteins
  • Metalloporphyrins
  • manganese(III)-tetrakis(4-benzoic acid)porphyrin
  • Manganese
  • RNA
  • Iron
  • Superoxide Dismutase
  • Iron Regulatory Protein 1