Friedreich`s ataxia : Pulling a therapy out of thin air

Tslil Ast ^1,2,3,4 Joshua Meisel ^1,2,3,4 Shachin Patra ⁵ Hong Wang ^1,2,3,4 Robert Grange ⁶ Sharon Kim ^1,2,3,4 Sarah Calvo ^1,2,3,4 Lauren Orefice ^3,4 Fumiaki Nagashima ⁶ Fumito Ichinose ⁶ Warren Zapol ⁶ Gary Ruvkun ⁴ David Barondeau ⁵ Vamsi Mootha ^1,2,3,4
¹Metabolic Disease Initiative, The Broad Institute
²Howard Hughes Medical Institute, Howard Hughes Medical Institute
³Department of Molecular Biology, Massachusetts General Hospital
⁴Harvard Medical School, Harvard Medical School
⁵Department of Chemistry, Texas A&m University
⁶Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital

Friedreich’s ataxia (FRDA) is the most common inherited ataxia, affecting an estimated 1:50,000 live births. This severe progressive neurodegenerative disease has no known therapies to date. It is caused by recessive mutations in the mitochondrial protein frataxin (FXN), which participates in the biosynthesis of Fe-S clusters and is considered essential for viability. Here we show that when grown in 1% ambient O₂, FXN null yeast, human cells, and nematodes are fully viable. Moreover, in a murine model of FRDA, breathing 11% O₂ attenuates the progression of ataxia, whereas breathing 55% O₂ hastens it. Moreover, this property is unique to FXN among the core Fe-S biosynthesis complex. In human cells, hypoxia restores steady-state levels of Fe-S clusters in both the mitochondria and cytosol. We combined cellular studies and in vitro reconstitution to shed light on the mechanisms by which hypoxia overcomes the genetic need for FXN, showing that hypoxia increases bioavailable iron levels as well as directly activate Fe-S synthesis. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.