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

Irazusta, Verónica Patricia; Moreno Cermeño, Armando J.; Cabiscol Català, Elisa; Ros Salvador, Joaquim; Tamarit Sumalla, Jordi

doi:https://doi.org/10.1016/j.freeradbiomed.2008.01.014

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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.

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

Is part of

Free Radical Biology and Medicine, 2008, vol. 44, núm. 9, p. 1712-1723