Yeast frataxin mutants display decreased superoxide dismutase activity crucial to promote protein oxidative damage

Free Radic Biol Med. 2010 Feb 1;48(3):411-20. doi: 10.1016/j.freeradbiomed.2009.11.010. Epub 2009 Dec 8.

Abstract

Iron overload is involved in several pathological conditions, including Friedreich ataxia, a disease caused by decreased expression of the mitochondrial protein frataxin. In a previous study, we identified 14 proteins selectively oxidized in yeast cells lacking Yfh1, the yeast frataxin homolog. Most of these were magnesium-binding proteins. Decreased Mn-SOD activity, oxidative damage to CuZn-SOD, and increased levels of chelatable iron were also observed in this model. This study explores the relationship between low SOD activity, the presence of chelatable iron, and protein damage. We observed that addition of copper and manganese to the culture medium restored SOD activity and prevented both oxidative damage and inactivation of magnesium-binding proteins. This protection was compartment specific: recovery of mitochondrial enzymes required the addition of manganese, whereas cytosolic enzymes were recovered by adding copper. Copper treatment also decreased Deltayfh1 sensitivity to menadione. Finally, a Deltasod1 mutant showed high levels of chelatable iron and inactivation of magnesium-binding enzymes. These results suggest that reduced superoxide dismutase activity contributes to the toxic effects of iron overloading. This would also apply to pathologies involving iron accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Copper / metabolism
  • Electrophoresis, Gel, Two-Dimensional
  • Gene Expression Regulation, Fungal
  • Iron / metabolism
  • Iron-Binding Proteins / genetics*
  • Iron-Binding Proteins / metabolism*
  • Manganese / metabolism
  • Mutation / genetics*
  • Oxidation-Reduction
  • Oxidative Stress
  • Proteins / chemistry*
  • Saccharomyces cerevisiae / metabolism*
  • Superoxide Dismutase / metabolism*

Substances

  • Iron-Binding Proteins
  • Proteins
  • frataxin
  • Manganese
  • Copper
  • Iron
  • Superoxide Dismutase