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Major targets of iron-induced protein oxidative damage in frataxin-deficient yeasts are magnesium-binding proteins

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Issue date
2008
Author
Irazusta, Verónica Patricia
Moreno Cermeño, Armando J.
Cabiscol Català, Elisa
Ros Salvador, Joaquim
Tamarit Sumalla, Jordi
Suggested citation
Irazusta, Verónica Patricia; Moreno Cermeño, Armando J.; Cabiscol Català, Elisa; Ros Salvador, Joaquim; Tamarit Sumalla, Jordi; . (2008) . Major targets of iron-induced protein oxidative damage in frataxin-deficient yeasts are magnesium-binding proteins. Free Radical Biology and Medicine, 2008, vol. 44, núm. 9, p. 1712-1723. https://doi.org/10.1016/j.freeradbiomed.2008.01.014.
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Abstract
Iron accumulation has been associated with several pathological conditions such as Friedreich ataxia. This human disorder is caused by decreased expression of frataxin. Iron-overload triggers oxidative stress, but the main targets of such stress are not known. In yeast cells lacking the frataxin ortholog YFH1, we have identified a set of 14 carbonylated proteins, which include mitochondrial ATP synthase, phosphoglycerate kinase, pyruvate kinase, and molecular chaperones. Interestingly, most of the target proteins are magnesium- and/or nucleotide-binding proteins. This key feature leads us to postulate that when iron accumulates, chelatable iron replaces magnesium at the corresponding metal-binding site, promoting selective damage to these proteins. Consistent with this hypothesis, in vitro experiments performed with pure pyruvate kinase and phosphoglycerate kinase showed that oxidation of these proteins can be prevented by magnesium and increased by the presence of ATP. Also, chelatable iron, which forms complexes with nucleotides, showed a sevenfold increase in Δyfh1 cells. Moreover, lowering chelatable iron in Δyfh1 cells by desferrioxamine prevented enzyme inactivation. As a general conclusion, we propose that magnesium bound to proteins is replaced by chelatable iron when this metal accumulates. This mechanism explains selective protein oxidation and provides clues for better understanding of iron-overloading pathologies.
URI
http://hdl.handle.net/10459.1/57158
DOI
https://doi.org/10.1016/j.freeradbiomed.2008.01.014
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Free Radical Biology and Medicine, 2008, vol. 44, núm. 9, p. 1712-1723
European research projects
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