Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

Cell. 2019 May 30;177(6):1507-1521.e16. doi: 10.1016/j.cell.2019.03.045. Epub 2019 Apr 25.

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 O2, 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% O2 attenuates the progression of ataxia, whereas breathing 55% O2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Caenorhabditis elegans / metabolism
  • Female
  • Friedreich Ataxia / metabolism
  • HEK293 Cells
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Iron / metabolism
  • Iron Regulatory Protein 2 / metabolism
  • Iron-Binding Proteins / metabolism*
  • Iron-Binding Proteins / physiology
  • Iron-Sulfur Proteins / metabolism*
  • Iron-Sulfur Proteins / physiology
  • K562 Cells
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Saccharomyces cerevisiae / metabolism
  • Sulfur / metabolism

Substances

  • ATF4 protein, human
  • Iron-Binding Proteins
  • Iron-Sulfur Proteins
  • Mitochondrial Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • frataxin
  • Activating Transcription Factor 4
  • Sulfur
  • Iron
  • Iron Regulatory Protein 2