Role of Oleic Acid in Mitigating the Iron-Induced Toxicity in Friedreich's Ataxia Cell Line Model

Abstract

Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a GAA trinucleotide repeat expansion in the frataxin (FXN) gene, leading to decreased frataxin expression. Frataxin is crucial for iron–sulfur cluster assembly and mitochondrial health. Its deficiency results in mitochondrial iron overload, impaired respiratory chain function, and increased production of reactive oxygen species (ROS), creating a cycle of oxidative stress and iron toxicity. This, in turn, increases neuronal vulnerability to ferroptosis, an iron-dependent form of lipid peroxidation–driven cell death. Our study investigated the protective role of oleic acid (OA), a monounsaturated fatty acid, against iron-induced ferroptosis in Friedreich’s ataxia (FRDA). Using SH-SY5Y neuroblastoma cells as a model system, we mimicked the iron overload by treating cells with ferric ammonium citrate (FAC). Supplementation with OA significantly improved cell viability, prompting us to examine the underlying mechanisms of protection further. We found that OA reduces oxidative stress by enhancing frataxin expression and upregulation of the NRF2 transcription factor, which upregulates the antioxidant pathway. The catalase, SOD1 and intracellular glutathione levels were upregulated, collectively reestablishing the redox balance and suppressing lipid peroxidation. In addition, OA supplementation preserved mitochondrial morphology and reduced Mito ROS, which were disrupted by FAC treatment. Together, these results demonstrate that OA protects neuronal cells against iron-induced ferroptosis by enhancing antioxidant defences, sustaining mitochondrial health, and suppressing ferroptotic signalling. Using OA supplements to target ferroptosis may offer a promising way to slow neurodegeneration and improve disease progression in FRDA and related neurological conditions caused by iron overload.