Abstract
Arsenite induces many critical effects associated with the formation of reactive oxygen species (ROS) through different mechanisms. We focused on Ca2+-dependent mitochondrial superoxide (mitoO2-.) formation and addressed questions on the effects of low concentrations of arsenite on the mobilization of the cation from the endoplasmic reticulum and the resulting mitochondrial accumulation. Using various differentiated and undifferentiated cell types uniquely expressing the inositol-1, 4, 5-triphosphate receptor (IP3R), or both the IP3R and the ryanodine receptor (RyR), we determined that expression of this second Ca2+ channel is an absolute requirement for mitoO2-. formation and for the ensuing mitochondrial dysfunction and downstream apoptosis. In arsenite-treated cells, RyR was recruited after IP3R stimulation and agonist studies provided an indirect indication for a close apposition between RyR and mitochondria. It was also interesting to observe that arsenite fails to promote mitochondrial Ca2+ accumulation, mitoO2-. formation and mitochondrial toxicity in RyR-devoid cells, in which the IP3R is in close contact with the mitochondria. We therefore conclude that low dose arsenite-induced mitoO2- formation, and the resulting mitochondrial dysfunction and toxicity, are prerequisite of cell types expressing the RyR in close apposition with mitochondria.
Highlights
We aim to investigate whether arsenite-induced mitoO2- formation, and the ensuing mitochondrial permeability transition (MPT)-dependent mitochondrial toxicity, is a prerogative of cell types with functional interactions between the IP3R and the ryanodine receptor (RyR), with this second channel in close apposition with mitochondria
We investigate whether the metalloid promotes mitochondrial Ca2+ accumulation and mitoO2- formation in cells that do not express the RyR, in which the IP3R is in close contact with the mitochondria
Characteristics of the experimental cell types In this study, we used undifferentiated U937 (U-U937) cells, which express both IP3R and RyR (Sugiyama et al 1994; Clementi et al 1998; Hosoi et al 2001; Guidarelli et al 2009), that can be differentiated to monocytes (D-U937) with concomitant downregulation of the RyR (Guidarelli et al 2009)
Summary
Arsenite is an important carcinogen and toxic compound (Flora 2011; Jomova et al 2011; Minatel et al 2018) that causes a plethora of effects in target cells, through its direct binding to some biomolecules (Chang et al 2012; Shen et al 2013) and/or via the intermediate formation of reactive oxygen species (ROS) (Flora 2011; Jomova et al 2011; Hu et al 2020). Given the relevance of this second event (Flora 2011; Jomova et al 2011; Hu et al 2020), it would be important to determine the mechanism whereby the metalloid promotes the formation of these species, to eventually establish a causal relationship with the effects generated in specific subcellular compartments. Shortlived species more likely generate relevant effects in the same sites of their formation, or in the close vicinity, thereby affecting the ensuing toxic response. The very large majority of the available studies provided a general indication of arsenite-induced ROS formation, with no systematic attempt to identify their origin, and the overall scenario remains poorly understood. Arsenite potentially activates at least two important mechanisms of ROS formation, and the reasons of the prevalence of a mechanism over the other remain poorly understood
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