Mutation in the Fe-S scaffold protein Isu bypasses frataxin deletion

Heeyong Yoon, Ramesh Golla, Emmanuel Lesuisse, Jayashree Pain, Jason E. Donald, Elise R. Lyver, Debkumar Pain, Andrew Dancis

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42 Scopus citations


Frataxin is a conserved mitochondrial protein deficient in patients with Friedreich's ataxia. Frataxin has been implicated in control of iron homoeostasis and Fe-S cluster assembly. In yeast or human mitochondria, frataxin interacts with components of the Fe-S cluster synthesis machinery, including the cysteine desulfurase Nfs1, accessory protein Isd11 and scaffold protein Isu. In the present paper, we report that a single amino acid substitution (methionine to isoleucine) at position 107 in the mature form of Isu1 restored many deficient functions in Δyfh1 or frataxin-depleted yeast cells. Iron homoeostasis was improved such that soluble/usable mitochondrial iron was increased and accumulation of insoluble/non-usable iron within mitochondria was largely prevented. Cytochromes were returned to normal and haem synthesis was restored. In mitochondria carrying the mutant Isu1 and no frataxin, Fe-S cluster enzyme activities were improved. The efficiency of newFe-S cluster synthesis in isolated mitochondria was markedly increased compared with frataxinnegative cells, although the response to added iron was minimal. The M107I substitution in the highly conserved Isu scaffold protein is typically found in bacterial orthologues, suggesting that a unique feature of the bacterial Fe-S cluster machinery may be involved. The mechanism by which the mutant Isu bypasses the absence of frataxin remains to be determined, but could be related to direct effects on Fe-S cluster assembly and/or indirect effects on mitochondrial iron availability.

Original languageEnglish (US)
Pages (from-to)473-480
Number of pages8
JournalBiochemical Journal
Issue number1
StatePublished - Jan 1 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


  • Frataxin
  • Haem
  • Iron
  • Iron-sulfur cluster (Fe-S cluster)
  • Mitochondrion


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