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  • br STAR Methods br Introduction Arsenite

    2021-10-19


    STAR★Methods
    Introduction Arsenite is a well-recognized toxic metalloid that commonly presents in the natural environment. Chronic exposure to arsenite can lead to a wide range of adverse health effects to human, including cancers, cardiovascular diseases, diabetes, skin lesion and neurodegenerative disorders (such as Alzheimer disease and Parkinson disease) (Naujokas et al., 2013). The loss of neurons in the cerebral cortex induced by arsenite has been extensively revealed as the main mechanism for the induction of arsenite neurotoxicity (Tolins et al., 2014). Increasing evidence also show that arsenite is able to trigger neuronal cell death mainly by apoptosis (Yen et al., 2012), autophagy (Lau et al., 2013) or necrosis (Selvaraj et al., 2013). However, the detailed mechanisms underlying how arsenite induces neuronal cell death remain unsolved. Ferroptosis is a newly recognized iron and reactive oxygen species (ROS)-dependent form of cell death (Dixon et al., 2012). It is remarkably distinct from other types of cell death at morphological, biochemical and genetic levels. It is characterized morphologically by the vanishing of mitochondria crista and rupture of mitochondrial membrane (Cao and Dixon, 2016; Yang and Stockwell, 2016). Ferroptosis can be triggered by some experimental compounds (erastin, sorafenib and artesnate etc.) in cancer apiii and certain normal cells, such as T cells, fibroblasts and neurons (Shimada et al., 2016; Xie et al., 2016). Misregulated ferroptosis has been implicated in numerous pathological processes, including neurotoxicity, neurodegenerative diseases (Do Van et al., 2016). Inhibition of ferroptosis by its specific inhibitor, such as ferrostatin-1 or liproxstatin-1, can significantly protect organisms from glutamate-induced neurotoxicity in cultured hippocampal slices (Dixon et al., 2014; Kang et al., 2014). Moreover, the inhibitors of ferroptosis also restore the number of healthy neurons in the animal model of Huntington’s disease (Skouta et al., 2014). In the periventricular leukomalacia, ferroptotic inhibitors markedly protect developing oligodendrocytes from cysteine deprivation (Stockwell et al., 2017). These findings together suggest that regulation of ferroptosis in neuronal cells may be a potential way to create a new opportunity for the treatment of neurodegenerative disorders. Up to now, whether arsenite is an inducer of ferroptosis in the neurons is still completely unknown. Intriguingly, it has been reported that arsenite induces the accumulation of lipid peroxidation as well as the production of ROS in several types of neuronal cells (Pachauri et al., 2013; Lu et al., 2014). Arsenite also activates the mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, leading to the mitochondrial dysfunction (Lu et al., 2014; Mao et al., 2016). These results imply that arsenite may trigger neuronal cell death by ferroptosis in vitro. Therefore, in the present study, C57BL/6J mice were treated with environmental related doses of arsenite for 6 months via drinking water, and the indicators of ferroptotic cell death were further determined. Our results demonstrated that arsenite induced ferroptotic cell death in neuron by accumulation of ROS and lipid peroxidation products, disruption of Fe2+ homeostasis, depletion of glutathione (GSH), superoxide dismutase (SOD) activities and adenosine triphosphate (ATP), inhibition of cysteine/glutamate antiporter, activation of mitogen-activated protein kinases (MAPKs) and mitochondrial voltage-dependent anion channels (VDACs) pathways, up-regulation of endoplasmic reticulum stress, all of which were involved in the process of ferroptosis. We further verify these findings by using cultured PC-12 cells. Together, our findings reveal that ferroptosis is linked to the neuronal cell death caused by arsenite exposure, indicating regulation of ferroptosis may be considered as a potential strategy for the treatment against arsenite-related neurodegenerative diseases.