Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

Tslil Ast, Joshua D. Meisel, Shachin Patra, Gary Ruvkun, David P. Barondeau, Vamsi K. Mootha; Cell , Volume 0 , Issue 0, Published: April 25, 2019, DOI:10.1016/j.cell.2019.03.045

Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O 2, 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 2 attenuates the progression of ataxia, whereas breathing 55% O 2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.