Friedreich ataxia is an inherited
neurodegenerative disease that leads to progressive disability. There is currently no effective treatment and patients die prematurely. The underlying genetic defect leads to reduced expression of the
mitochondrial protein frataxin.
Frataxin insufficiency causes
mitochondrial dysfunction and ultimately cell death, particularly in peripheral sensory ganglia. There is an inverse correlation between the amount of residual
frataxin and the severity of
disease progression; therefore, therapeutic approaches aiming at increasing
frataxin levels are expected to improve patients' conditions. We previously discovered that a significant amount of
frataxin precursor is degraded by the
ubiquitin/
proteasome system before its functional mitochondrial maturation. We also provided evidence for the therapeutic potential of small molecules that increase
frataxin levels by docking on the
frataxin ubiquitination site, thus preventing
frataxin ubiquitination and degradation. We called these compounds
ubiquitin-competing molecules (UCM). By extending our search for effective UCM, we identified a set of new and more potent compounds that more efficiently promote
frataxin accumulation. Here we show that these compounds directly interact with
frataxin and prevent its ubiquitination. Interestingly, these UCM are not effective on the
ubiquitin-resistant
frataxin mutant, indicating their specific action on preventing
frataxin ubiquitination. Most importantly, these compounds are able to promote
frataxin accumulation and
aconitase rescue in cells derived from patients, strongly supporting their therapeutic potential.