Iron-sulfur glutaredoxin 2 protects oligodendrocytes against damage induced by nitric oxide release from activated microglia

Glia. 2017 Sep;65(9):1521-1534. doi: 10.1002/glia.23178. Epub 2017 Jun 15.


Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glutaredoxin 2 inhibits peroxynitrite formation by transforming nitric oxide into dinitrosyl-diglutathionyl-iron-complexes. Glutaredoxin 2 levels influence both survival rates of primary oligodendrocyte progenitor cells and preservation of myelin structure in cerebellar organotypic slice cultures challenged with activated microglia or nitric oxide donors. Of note, glutaredoxin 2-mediated protection is not linked to its enzymatic activity as oxidoreductase, but to the disassembly of its uniquely coordinated iron-sulfur cluster using glutathione as non-protein ligand. The protective effect of glutaredoxin 2 is connected to decreased protein carbonylation and nitration. In line, brain lesions of mice suffering from experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, show decreased glutaredoxin 2 expression and increased nitrotyrosine formation indicating that this type of protection is missing in the inflamed central nervous system. Our findings link inorganic biochemistry to neuroinflammation and identify glutaredoxin 2 as a protective factor against neuroinflammation-mediated myelin damage. Thus, improved availability of glutathione-coordinated iron-sulfur clusters emerges as a potential therapeutic approach in inflammatory demyelination.

Keywords: dinitrosyl-iron-complex; glutathione; myelin; oxidation; oxidoreductase.

MeSH terms

  • Animals
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Escherichia coli
  • Female
  • Glutaredoxins / genetics
  • Glutaredoxins / metabolism*
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice, Inbred C57BL
  • Microglia / metabolism*
  • Microglia / pathology
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neuroprotection / physiology
  • Nitric Oxide / metabolism*
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Peroxynitrous Acid / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Schistosoma japonicum
  • Tissue Culture Techniques


  • GLRX2 protein, human
  • Glrx2 protein, mouse
  • Glutaredoxins
  • Recombinant Proteins
  • Peroxynitrous Acid
  • Nitric Oxide
  • Glutathione Transferase