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Cell DOI:10.1016/j.cell.2019.03.045

Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis.

Publication TypeJournal Article
Year of Publication2019
AuthorsAst, 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
JournalCell
Date Published2019 Apr 23
ISSN1097-4172
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 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.

DOI10.1016/j.cell.2019.03.045
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31031004?dopt=Abstract

Alternate JournalCell
PubMed ID31031004