Normal and Friedreich ataxia cells express different isoforms of frataxin with complementary roles in iron-sulfur cluster assembly

Oleksandr Gakh, Tibor Bedekovics, Samantha F. Duncan, Douglas Y. Smith IV, Donald S. Berkholz, Grazia Isaya

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused by insufficient expression of frataxin (FXN), a mitochondrial iron-binding protein required for Fe-S cluster assembly. The development of treatments to increase FXN levels in FRDA requires elucidation of the steps involved in the biogenesis of functional FXN. The FXN mRNA is translated to a precursor polypeptide that is transported to the mitochondrial matrix and processed to at least two forms, FXN42-210 and FXN81-210. Previous reports suggested that FXN42-210 is a transient processing intermediate, whereas FXN81-210 represents the mature protein. However, we find that both FXN42-210 and FXN81-210 are present in control cell lines and tissues at steady-state, and that FXN 42-210 is consistently more depleted than FXN81-210 in samples from FRDA patients. Moreover, FXN42-210 and FXN 81-210 have strikingly different biochemical properties. A shorter N terminus correlates with monomeric configuration, labile iron binding, and dynamic contacts with components of the Fe-S cluster biosynthetic machinery, i.e. the sulfur donor complex NFS1·ISD11 and the scaffold ISCU. Conversely, a longer N terminus correlates with the ability to oligomerize, store iron, and form stable contacts with NFS1·ISD11 and ISCU. Monomeric FXN81-210 donates Fe2+ for Fe-S cluster assembly on ISCU, whereas oligomeric FXN42-210 donates either Fe2+ or Fe3+. These functionally distinct FXN isoforms seem capable to ensure incremental rates of Fe-S cluster synthesis from different mitochondrial iron pools. We suggest that the levels of both isoforms are relevant to FRDA pathophysiology and that the FXN81-210/FXN42-210 molar ratio should provide a useful parameter to optimize FXN augmentation and replacement therapies.

Original languageEnglish (US)
Pages (from-to)38486-38501
Number of pages16
JournalJournal of Biological Chemistry
Issue number49
StatePublished - Dec 3 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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