Biochemical Journal

Research article

Frataxin-bypassing Isu1: characterization of the bypass activity in cells and mitochondria

Heeyong Yoon , Simon A. B. Knight , Alok Pandey , Jayashree Pain , Yan Zhang , Debkumar Pain , Andrew Dancis


Frataxin is a conserved mitochondrial protein, and deficiency underlies the neurodegenerative disease Friedreich's ataxia. Frataxin interacts with the core machinery for Fe–S cluster assembly in mitochondria. Recently we reported that in frataxin-deleted yeast strains, a spontaneously occurring mutation in one of two genes encoding redundant Isu scaffold proteins, bypassed the mutant phenotypes. In the present study we created strains expressing a single scaffold protein, either Isu1 or the bypass mutant M107I Isu1. Our results show that in the frataxin-deletion strain expressing the bypass mutant Isu1, cell growth, Fe–S cluster protein activities, haem proteins and iron homoeostasis were restored to normal or close to normal. The bypass effects were not mediated by changes in Isu1 expression level. The persulfide-forming activity of the cysteine desulfurase was diminished in the frataxin deletion (∆yfh1 ISU1) and was improved by expression of the bypass Isu1 (∆yfh1 M107I ISU1). The addition of purified bypass M107I Isu1 protein to a ∆yfh1 lysate conferred similar enhancement of cysteine desulfurase as did frataxin, suggesting that this effect contributed to the bypass mechanism. Fe–S cluster-forming activity in isolated mitochondria was stimulated by the bypass Isu1, albeit at a lower rate. The rescuing effects of the bypass Isu1 point to ways that the core defects in Friedreich's ataxia mitochondria can be restored.

  • cysteine desulfurase
  • eukaryote
  • frataxin
  • iron–sulfur
  • Isu1 scaffold
  • mitochondrion

Abbreviations: Aft1/2, activator of ferrous transport 1/2; Ccp1, cytochrome c peroxidase; Cyc1, cytochrome c; Isd11, iron–sulfur desulfurase-interacting protein; Nfs1, NiFS-like 1; Ni-NTA, Ni2+-nitrilotriacetate

View Full Text

Log in through your institution