PT  - JOURNAL ARTICLE
AU  - M. Grazia Cotticelli
AU  - Shujuan Xia
AU  - Daniel Lin
AU  - Taehee Lee
AU  - Leila Terrab
AU  - Peter Wipf
AU  - Donna Huryn
AU  - Robert Wilson
TI  - Ferroptosis as a novel therapeutic target for Friedreich's ataxia
AID  - 10.1124/jpet.118.252759
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.252759
4099  - http://jpet.aspetjournals.org/content/early/2019/01/11/jpet.118.252759.short
4100  - http://jpet.aspetjournals.org/content/early/2019/01/11/jpet.118.252759.full
AB  - Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (KIKO) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors SRS11-92 and Fer-1, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis (BSO), whereas caspase-3 inhibitors failed to show significant biological activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.