Friedreich ataxia is a human neurodegenerative and myocardial disease caused by decreased expression of the mitochondrial protein frataxin. Proteomic analysis of the mutant yeast model of Friedreich ataxia presented in this paper reveals that these cells display increased amounts of proteins involved in antioxidant defenses, including manganese-superoxide dismutase. This enzyme shows, however, lower activity than that found in wild type cells. Our results indicate that this lack of activity is a consequence of cellular manganese deficiency, because in manganese-supplemented cultures, cell manganese content, and manganese-superoxide dismutase activity were restored. One of the hallmarks of Friedreich ataxia is the decreased activity of iron/sulfur-containing enzymes. The activities of four enzymes of this group (aconitase, glutamate synthase, succinate dehydrogenase, and isopropylmalate dehydratase) have been analyzed for the effects of manganese supplementation. Enzyme activities were recovered by manganese treatment, except for aconitase, for which, a specific interaction with frataxin has been demonstrated previously. Similar results were obtained when cells were grown in iron-limited media suggesting that manganese-superoxide dismutase deficiency is a consequence of iron overload. In conclusion, these data indicate that generalized deficiency of iron-sulfur protein activity could be a consequence of manganese-superoxide dismutase deficiency, and consequently, it opens new strategies for Friedreich ataxia treatment.

• PMID: 16510442
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Irazusta V, Cabiscol E, Reverter-Branchat G, Ros J, Tamarit J

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