Carla Lima
| Targeting Mitochondrial Iron Dysregulation in Friedreich’s Ataxia Using Novel Chelators |
| Carla Lima1, Mariana Casteloa1, Daniel Chavarria2, Lisa Sequeira2, Fernando Cagide2, Fernanda Borges1,2, Sofia Benfeito2 1 RISE-Health, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal 2 RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal |
| Abstract Friedreich’s Ataxia (FRDA; ORPHA:95) is an inherited and progressive neurodegenerative disease, being characterized by sensory loss and hypertrophic cardiomyopathy. It represents the most common form of inherited ataxia with an autosomal-recessive inheritance pattern, affecting 1 in 50.000 individuals worldwide. The disease is typically diagnosed in childhood (2-3 years) or early adulthood (˃25 years) and often progresses into a fatal outcome. FRDA is associated with reduced levels of frataxin (FXN), a mitochondrial protein that plays a key role as iron chaperone in the synthesis of heme and iron-sulfur clusters (ISCs). The FXN decreased levels are caused by homozygous hyperexpansion of guanine-adenine-adenine (GAA) triplets in the first intron of the FXN gene on chromosome 9. Sustained reduction of FXN amount leads to increased levels of mitochondrial labile iron, impairments in ISC biogenesis, reduction in heme biosynthesis and defective activities of aconitase and respiratory chain complexes I, II and III. These events result in ROS overproduction, reduced ATP production and, ultimately, in mitochondrial dysfunction. 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 However, DFP lacks mitochondrial specificity and results from its phase II trial for FRDA (NCT00897221) remain unpublished. So, we hypothesize that selectively targeting iron chelators to mitochondria can prevent iron-induced toxicity, mitochondrial dysfunction and ferroptosis. In this way, a new library of compounds based on DFP scaffold was synthesized to improve mitochondrial targeting, combining iron-chelating and antioxidant properties to address mitochondrial dysfunction and prevent ferroptosis in FRDA. After structural characterization, the compounds were evaluated for cytotoxicity in various cell lines, followed by assessment of their ability to reverse damage induced by ferroptosis. The results obtained so far will be presented in this communication. |
| References [1] Cotticelli, M.G., et al., Ferroptosis as a Novel Therapeutic Target for Friedreich’s Ataxia. J. Pharmacol. Exp. Ther. 2019, 369(1): p. 47. [2] Johnson, J., et al., Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Arch. Biochem. Biophys., 2021, 702, p. 108698. Acknowledgments: This work was funded by FEDER funds through the Operational Program Competitiveness Factors COMPETE and national funds by the FCT-Foundation for Science and Technology under research grants for RISE-Health (UID/06397/2025,) and RESTORE (COMPETE2030-FEDER-00776500 and 2023.17955.ICDT). This work was also funded by project IMPULSE and services of EU-OPENSCREEN (Horizon Europe: 101132028; DOI: 10.3030/101132028). M.C. (2022.13356.BD), C.L. (UI/BD/154557/2023) grants and D.C. (2024.07926.CEECIND) and S.B. (2023.06106.CEECIND/CP2833/CT0003) contracts were also supported by FCT and FEDER/COMPETE funds. |