Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Apr 30

PMID 31031004

Citations 56

Authors

Tslil Ast

Joshua D Meisel

Shachin Patra

Hong Wang

Robert M H Grange

Sharon H Kim

Sarah E Calvo

Lauren L Orefice

Fumiaki Nagashima

Fumito Ichinose

Warren M Zapol

Gary Ruvkun

David P Barondeau

Vamsi K Mootha

Affiliations

Soon will be listed here.

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.

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