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

This study shows that conditions that result in increased mitochondrial reactive oxygen species (ROS) in yeast or mammalian cell culture give rise to increased turnover of frataxin, but not of other iron-sulfur cluster (ISC) synthesis proteins. The authors demonstrate that the mitochondrial Lon protease is involved in frataxin degradation and that iron export through the mitochondrial metal transporter Mmt1 protects yeast frataxin from degradation. When FRDA fibroblasts were grown in media containing elevated iron, mitochondrial ROS increased and frataxin decreased compared to WT fibroblasts. Furthermore, a library of FDA-approved compounds was screened and 38 compounds that increased yeast frataxin levels identified, 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). The authors 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.

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