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.