Posttranslational Regulation of Mitochondrial Frataxin and Identification of Compounds that Increase Frataxin Levels in Friedreich’s Ataxia

Peter T. Hackett, Xuan Jia, Liangtao Li, Diane M. Ward; Journal of Biological Chemistry, 2022, 101982, ISSN 0021-9258, doi:10.1016/j.jbc.2022.101982. 

We screened a library of FDA-approved compounds and identified 38 compounds that increased yeast frataxin levels, including the azole Bifonazole, antiparasitic Fipronil, anti-tumor compound Dibenzoylmethane (DBM), antihypertensive 4-hydroxychalcone (4’-OHC), and a non-specific anion channel inhibitor 4,4-diisothiocyanostilbene-2,2-sulfonic acid (DIDS). We show that top hits 4’-OHC and DBM increased mRNA levels of transcription factor Nrf2 in FRDA patient-derived fibroblasts, as well as downstream antioxidant targets thioredoxin (TXN), glutathione reductase (GSR), and superoxide dismutase 2 (SOD2). Taken together, these findings reveal that FRDA progression may be in part due to oxidant-mediated decreases in frataxin, and that some approved compounds may be effective in increasing mitochondrial frataxin in FRDA, delaying disease progression

Posttranslational Regulation of Mitochondrial Frataxin and Identification of Compounds that Increase Frataxin Levels in Friedreich’s Ataxia