Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis Academic Article uri icon


  • Friedreich's ataxia (FRDA) is a devastating, multisystemic disorder caused by recessive mutations in the mitochondrial protein frataxin (FXN). FXN participates in the biosynthesis of Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O2, FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in┬ávitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis. In a mouse model of FRDA, breathing 11% O2 attenuates the progression of ataxia, whereas breathing 55% O2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.

altmetric score

  • 51.45

author list (cited authors)

  • Ast, T., Meisel, J. D., Patra, S., Wang, H., Grange, R., Kim, S. H., ... Mootha, V. K.

citation count

  • 35

publication date

  • April 2019

published in