INTRODUCTION: Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron (DN) loss in the substantia nigra. Dysregulated iron metabolism, mitochondrial calcium (Ca²⁺) overload, and oxidative stress contribute to neurodegeneration. Ferroptosis, a form of regulated cell death dependent on iron and lipid peroxidation, has been implicated in PD pathogenesis.

AIM(S): To investigate ferroptosis in neuronal cells carrying pathogenic LRRK2 mutations and assess whether inhibition of the MCU alleviates ferroptosis-related damage.

METHOD(S): Ferroptosis was induced using RSL3 in LRRK2-mutant (G2019S) and control human neuronal cells. The cells were obtained from iPSc lines. Mitochondrial calcium was modulated using Ru360, a specific MCU inhibitor. Lipid peroxidation levels were measured using C11-BODIPY staining, and intracellular iron (Fe²⁺) content was assessed using Assay Kit (Colorimetric). Expression of ferroptosis markers (GPX4, NRF2, HMGB1, HMOX1) was evaluated by qPCR and Western blot.

RESULTS: LRRK2-mutant neurons showed increased susceptibility to RSL3 compared to control cells, with elevated lipid peroxidation and iron accumulation. These cells also displayed downregulation of GPX4 and HMGB1 and upregulation of NRF2 and HMOX1. MCU inhibition with Ru360 restored redox balance, decreased lipid peroxidation, and improved neuronal survival, suggesting attenuation of ferroptosis.

CONCLUSIONS: Ferroptosis contributes to neurodegeneration in LRRK2-linked PD. MCU inhibition protects neurons likely by modulating ferroptosis pathways. Targeting MCU may represent a promising therapeutic approach for PD.

FINANCIAL SUPPORT: This study was supported by the National Science Centre (NCN), OPUS 25, project no. 2023/49/B/NZ4/02744 to JK).