Addressing Mitochondrial Iron Dysregulation in Friedreich’s Ataxia

Introduction: Friedreich’s Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by impaired muscle coordination and hypertrophic cardiomyopathy, affecting 1 in 50,000 individuals worldwide. It results from GAA triplet expansion in the FXN gene, reducing frataxin levels and causing mitochondrial dysfunction, oxidative stress and oxytosis/ferroptosis, a form of iron-dependent regulated cell death. Although the FDA-approved omaveloxolone slows disease progression via NRF2 activation, its association with elevated liver enzymes limits its clinical use, and no treatments currently effectively address the underlying causes of FRDA. Rationale: Deferiprone (DFP), an iron chelator, has demonstrated potential in managing FRDA by crossing physiological barriers and targeting intracellular iron pools. However, DFP lacks mitochondrial specificity and results from its phase II trial for FRDA (NCT00897221) remain unpublished. Therefore, we hypothesize that selectively targeting iron chelators to mitochondria can prevent iron-induced toxicity, mitochondrial dysfunction and oxytosis/ferroptosis. Objectives: We aimed to design and synthesize DFP-based compounds to improve mitochondrial targeting, combining iron chelating and antioxidant properties to address mitochondrial dysfunction and prevent oxytosis/ferroptosis in FRDA. Methods: DFP derivatives were synthesized and evaluated for antioxidant activity using the ORAC assay to measure the peroxyl radical scavenging activity. Iron chelating properties were recorded using UV-Vis spectroscopy in the absence/presence of FeSO_4. The active compounds were further tested for their ability to protect neuronal cells (HT22) from oxytosis/ferroptosis induced by glutamate, erastin or RSL3 insults. Results: DFP derivatives exhibited similar antioxidant activity to the parent DFP, indicating that structural modifications did not alter peroxyl radical neutralization and effectively chelated Fe²⁺. Some compounds showed significant protection against oxytosis/ferroptosis in HT22 cells, with the best compound presenting EC₅₀s of 5.10 µM, 6.0 µM and 5.8 µM against glutamate, erastin and RSL3, respectively. Conclusions: Novel DFP derivatives provide a multitarget strategy to address mitochondrial dysfunction in FRDA, offering a promising new safety class of therapeutic agents with combined iron chelation, antioxidant and neuroprotective properties.