|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Ast, T, Meisel, JD, Patra, S, Wang, H, Grange, RMH, Kim, SH, Calvo, SE, Orefice, LL, Nagashima, F, Ichinose, F, Zapol, WM, Ruvkun, G, Barondeau, DP, Mootha, VK|
|Date Published||2019 Apr 23|
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 O, 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% O attenuates the progression of ataxia, whereas breathing 55% O hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.