Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis.

ABSTRACT: 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 vitro 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 brea

SUBMITTER: Ast T 

PROVIDER: S-EPMC6911770 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature