Tuesday, April 26, 2022

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