Changes in mitochondrial glutathione levels and protein thiol oxidation in ∆yfh1 yeast cells and the lymphoblasts of patients with Friedreich's ataxia

Biochim Biophys Acta. 2012 Feb;1822(2):212-25. doi: 10.1016/j.bbadis.2011.11.003. Epub 2011 Nov 11.


Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by low levels of the mitochondrial protein frataxin. The main phenotypic features of frataxin-deficient human and yeast cells include iron accumulation in mitochondria, iron-sulfur cluster defects and high sensitivity to oxidative stress. Frataxin deficiency is also associated with severe impairment of glutathione homeostasis and changes in glutathione-dependent antioxidant defenses. The potential biological consequences of oxidative stress and changes in glutathione levels associated with frataxin deficiency include the oxidation of susceptible protein thiols and reversible binding of glutathione to the SH of proteins by S-glutathionylation. In this study, we isolated mitochondria from frataxin-deficient ∆yfh1 yeast cells and lymphoblasts of FRDA patients, and show evidence for a severe mitochondrial glutathione-dependent oxidative stress, with a low GSH/GSSG ratio, and thiol modifications of key mitochondrial enzymes. Both yeast and human frataxin-deficient cells had abnormally high levels of mitochondrial proteins binding an anti-glutathione antibody. Moreover, proteomics and immunodetection experiments provided evidence of thiol oxidation in α-ketoglutarate dehydrogenase (KGDH) or subunits of respiratory chain complexes III and IV. We also found dramatic changes in GSH/GSSG ratio and thiol modifications on aconitase and KGDH in the lymphoblasts of FRDA patients. Our data for yeast cells also confirm the existence of a signaling and/or regulatory process involving both iron and glutathione.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism
  • Friedreich Ataxia / metabolism*
  • Glutathione / metabolism*
  • Glutathione Disulfide / metabolism
  • Homeostasis / physiology
  • Humans
  • Iron / metabolism
  • Iron-Binding Proteins / metabolism*
  • Lymphocytes / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • Protease La / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / physiology
  • Saccharomyces cerevisiae / metabolism
  • Sulfhydryl Compounds / metabolism*


  • Antioxidants
  • Iron-Binding Proteins
  • Mitochondrial Proteins
  • Sulfhydryl Compounds
  • frataxin
  • Iron
  • Protease La
  • Proteasome Endopeptidase Complex
  • Glutathione
  • Glutathione Disulfide