Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

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 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. [Display omitted] •FXN null yeast, human cells, and nematodes are fully viable in ambient 1% O2•Hypoxia restores steady-state levels of Fe-S clusters in FXN null cells•Hypoxia acts by directly activating Fe-S synthesis and increasing bioavailable iron•In a murine model of FXN deficiency, ambient oxygen affects the progression of ataxia Hypoxia promotes survival of in vivo models of Friederich’s ataxia by restoring the necessary signaling pathways for Fe-S metabolism associated with mitochondrial function.