Decreased SOD activity triggers protein oxidative damage in frataxin-deficient yeasts.

VERÓNICA IRAZUSTA; ARMANDO MORENO-CERMEÑO; JOAQUIM ROS; JORDI TAMARIT

Valencia-España

Simposio; INTERNATIONAL SYMPOSIUM ON RARE DISEASED. INHERETE NEUROMUSCULAR DISEASES: TRANSLATION FROM PATHOMECHANISMS TO THERAPIES; 2008

Iron-overload is involved in several pathological conditions such as Friedreich ataxia, a human disorder caused by decreased expression of frataxin. Frataxin deficient yeasts are exposed to oxidative stress due to both iron-overload and decreased superoxide dismutase activity. Previously, by analyzing protein carbonylation in 2D-blots, we identified oxidatively damaged proteins in yeast cells lacking the frataxin ortholog Yfh1. Most of the target proteins were magnesium and/or nucleotide-binding proteins such as ATP synthase, phosphoglycerate kinase and pyruvate kinase. These proteins were damaged due to the presence of increased levels of chelatable iron in Dyfh1 cells. In the present work we have investigated the relationship between decreased superoxide dismutase activity, chelatable iron and protein damage. Both increased levels of chelatable iron and pyruvate kinase deficiency were found in Dsod1 cells. Also, pyruvate kinase and ATP synthase activities were restored after recovering SOD activity by supplementing the growth media with cupper and/or manganese. Decreasing chelatable iron by desferrioxamine treatment also restored pyruvate kinase activity. These results indicate that decreased SOD activity leads to the formation of chelatable iron, which in turn triggers the formation of reactive oxygen species that can promote protein oxidation.