Major targets of iron-induced protein oxidative damage in frataxin-deficient yeasts are magnesium-binding proteins
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2008Author
Irazusta, Verónica Patricia
Moreno Cermeño, Armando J.
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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Show full item recordAbstract
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.
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Free Radical Biology and Medicine, 2008, vol. 44, núm. 9, p. 1712-1723European research projects
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