Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

Nat Commun. 2015 Jan 19;6:5686. doi: 10.1038/ncomms6686.


Friedreich's ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron-sulfur (Fe-S) cluster biogenesis. In mammals, the primary steps of Fe-S cluster assembly are performed by the NFS1-ISD11-ISCU complex via the formation of a persulfide intermediate on NFS1. Here we show that frataxin modulates the reactivity of NFS1 persulfide with thiols. We use maleimide-peptide compounds along with mass spectrometry to probe cysteine-persulfide in NFS1 and ISCU. Our data reveal that in the presence of ISCU, frataxin enhances the rate of two similar reactions on NFS1 persulfide: sulfur transfer to ISCU leading to the accumulation of a persulfide on the cysteine C104 of ISCU, and sulfur transfer to small thiols such as DTT, L-cysteine and GSH leading to persulfuration of these thiols and ultimately sulfide release. These data raise important questions on the physiological mechanism of Fe-S cluster assembly and point to a unique function of frataxin as an enhancer of sulfur transfer within the NFS1-ISD11-ISCU complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon-Sulfur Lyases / chemistry
  • Carbon-Sulfur Lyases / metabolism*
  • Chromatography, Gel
  • Chromatography, High Pressure Liquid
  • Cysteine / chemistry
  • Cysteine / metabolism
  • Glutathione / chemistry
  • Glutathione / metabolism
  • Humans
  • Iron-Binding Proteins / chemistry
  • Iron-Binding Proteins / metabolism*
  • Mass Spectrometry
  • Software
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / metabolism*
  • Sulfides / chemistry
  • Sulfides / metabolism


  • Iron-Binding Proteins
  • Sulfhydryl Compounds
  • Sulfides
  • frataxin
  • persulfides
  • Carbon-Sulfur Lyases
  • NFS1 protein, human
  • Glutathione
  • Cysteine