Arsenite enhances ERO1α expression via ryanodine receptor dependent and independent mechanisms

Abstract

Arsenite is a potent carcinogen and toxic compound inducing an array of deleterious effects via different mechanisms, which include the Ca²⁺-dependent formation of reactive oxygen species. The mechanism whereby the metalloid affects Ca²⁺ homeostasis involves an initial stimulation of the inositol 1, 4, 5-triphosphate receptor, an event associated with an endoplasmic reticulum (ER) stress leading to increased ERO1α expression, and ERO1α dependent activation of the ryanodine receptor (RyR). Ca²⁺ release from the RyR is then critically connected with the mitochondrial accumulation of Ca²⁺. We now report that the resulting formation of mitochondrial superoxide triggers a second mechanism of ER stress dependent ERO1α expression, which however fails to impact on Ca²⁺ release from the RyR or, more generally, on Ca²⁺ homeostasis. Our results therefore demonstrate that arsenite stimulates two different and sequential mechanisms leading to increased ERO1α expression with different functions, possibly due to their different subcellular compartmentalization.

Keywords: Arsenite; ER stress; ERO1α; Inositol-1, 4, 5-triphosphate receptor; Mitochondrial superoxide; Ryanodine receptor.