Figure 1.

Crosstalk between arsenite-induced mitochondrial ROS, ER stress, and Nrf2. Arsenite promotes mitoO₂^•− formation via a mechanism requiring interactions with the mitochondrial respiratory chain and an accumulation of Ca²⁺ in these organelles. The metalloid initially stimulates Ca²⁺ release from the IP₃R, which, although not directly taken up by the mitochondria, nevertheless contributes to this event via RyR stimulation. Indeed, due to the close apposition with the mitochondria, only the fraction of Ca²⁺ the RyR can be taken up by the mitochondria. Cells uniquely expressing the IP₃R, in which these channels are in close contact with the mitochondria, failed to generate mitoO₂^•− in response to arsenite. RyR activation was regulated by ERO1α and the resulting mitochondrial accumulation of Ca²⁺ was critical for the formation of mitoO₂^•. In this perspective, while the ER stress response appears upstream to mitoO₂^•− formation, it is nevertheless reasonable to predict that persistent mitoO₂^•−-derived H₂O₂ promotes mitochondrial dysfunction and toxicity. The early ER stress response was also critically connected through mitoO₂^• formation with the triggering of the Nrf2 cytoprotective signaling, which indeed significantly mitigated and delayed the onset of MPT-dependent apoptosis.