Ferrostatin-1 mitigates cellular damage in a ferroptosis-like environment in Caenorhabditis elegans

Abstract

Although iron (Fe) is the most biologically abundant transition metal, it is highly toxic when it accumulates as Fe2þ, forming a labile Fe pool and favoring the Fenton reaction. This oxidative scenario leads to a type of caspase-independent programmed cell death, referred to as ferroptosis, where following processes take place: (i) Fe2þ overload, (ii) glutathione peroxidase 4 inactivation, (iii) lipid peroxidation, and (iv) glutathione depletion. The present study sought to evaluate the consequences of Fe2þ administration on ferroptosis induction in Caenorhabditis elegans. We demonstrated higher mortality, increased lipid peroxidation, reduced glutathione peroxidase activity, and morphological damage in dopaminergic neurons upon Fe2þ overload. Pharmacological intervention at the level of lipid peroxidation with ferrostatin-1 (250 μM) mitigated the damage and returned the biochemical parameters to basal levels, revealing the potential of this therapeutical approach. Finally, to assess the relationship between ferroptosis and dopamine in a Parkinsonian background, we evaluated the UA44 worm strain which overexpresses the alpha-synuclein protein in cherry-labeled dopaminergic neurons. We demonstrated that Fe2þ administration reduced lethality associated with similar alterations in biochemical and dopaminergic morphological parameters in wild-type animals. These experiments provide mechanistic-based evidence on the efficacy of a pharmacological approach to mitigate the physiological, biochemical, and morphological consequences of Fe2þ overload. At the same time, they encourage further research on the impact of the combined effects resulting from the genetic background and dopamine signaling in a Parkinsonian phenotype.