Copper exposure induces neurotoxicity through ferroptosis in C. elegans

Copper, as a vital trace element and ubiquitous environmental pollutant, exhibits a positive correlation with the neurodegenerative diseases. Recent studies have highlighted ferroptosis's significance in heavy metal-induced neurodegenerative diseases, yet its role in copper-related neurotoxicity remains unclear. This study aimed to investigate the role of ferroptosis in copper-induced neurotoxicity. Previously, we established that copper induced motor behaviors inhibition and neuronal degeneration through oxidative stress in Caenorhabditis elegans (C. elegans). This study revealed that the behavior inhibition (head thrash, body bends, pumping frequency and defecation interval) and neuronal degeneration (GABAergic neurons and dopaminergic neurons) in copper-treated nematodes were reversed by the ferroptosis inhibitor Fer-1. Additionally, copper treatment increased the Fe²⁺ level and MDA content, and decreased GSH content, suggesting copper activated the ferroptosis in C. elegans. Furthermore, studies found that copper exposure altered the expression of ferroptosis-related genes gpx-1, ftn-1, and acs-17 in C. elegans. The results showed RNAi of gpx-1 and RNAi of ftn-1 significantly promoted Cu-induced neurotoxicity, while the RNAi of acs-17 appeared to rescue the Cu-induced ferroptosis and neurotoxicity. In conclusion, Cu might induce behavior inhibition and neuronal degeneration through ferroptosis in C. elegans. The findings of this study provided new insights in the mechanisms underlying Cu-induced neurotoxicity.