Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis.

Cell
Authors
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.

Year of Publication
2019
Journal
Cell
Date Published
2019 Apr 23
ISSN
1097-4172
DOI
10.1016/j.cell.2019.03.045
PubMed ID
31031004
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