Friedreich ataxia: the oxidative stress paradox

Abstract

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.

Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth

“…These findings lend some support to recently published findings in frataxin knock-out mice questioning the link between frataxin deficiency and ROS accumulation (25).…”

“…Nevertheless, recent findings question the primary relevance of ROS formation in frataxin deficiency (25). To evaluate whether overexpression of frataxin in colon cancer cells might influence the endogenous production of ROS, intracellular oxidation of dihydro-dichloro-fluorescein was quantified and found unaltered.…”

Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia

“…In this context, it might be informative in future experiments to examine the impact of SOD1 or SOD2 augmentation on cytoplasmic and mitochondrial aconitase activities in DFHdeficient flies. In keeping with our observations, it has been reported that increased expression of SOD1 and exposure to a small-molecule SOD2 mimetic does not improve murine FRDA cardiomyopathy (44).…”

Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

“…In patients and various models of Friedreich's ataxia, Fe-S cluster biogenesis and iron metabolism are impaired 2,3 . Initial studies on eukaryotic and prokaryotic FXNs suggested roles in iron storage 4 , delivery 5 and detoxification 6 , but the physiological relevance of these functions has been questioned [7][8][9][10] . Recent studies instead point to a direct role of FXN in Fe-S cluster assembly [11][12][13][14] .…”