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The present study used human myeloid leukemia U937 cells, a versatile promonocytic cellular system that, based on its endoplasmic reticulum (ER)/mitochondria functional relationships, responds to low micromolar concentrations of arsenite with a single, defined mechanism of superoxide (O 2  -. ) formation. Under these conditions, we observe an initial Ca 2+ mobilization from the ER associated with the mitochondrial accumulation of the cation, which is followed by Ca 2+ -dependent mitochondrial O 2  -. (mitoO 2  -. ) formation. These events, which were barely detectable after 3 hours, were better appreciated at 6 hours. We found that markedly shorter exposure to arsenite and lower concentrations of arsenite are required to induce extensive O 2  - formation in cells supplemented with inositol-1,4,5-trisphosphate receptor (IP 3 R) or ryanodine receptor (RyR) agonists. Indeed, nanomolar arsenite induced maximal O 2  -. formation after only 10 minutes of exposure, and this response was uniquely dependent on the enforced mitochondrial Ca 2+ accumulation. The dramatic anticipation of and sensitization to the effects of arsenite caused by the IP 3 R or RyR agonists were accompanied by a parallel significant genotoxic response in the absence of detectable mitochondrial dysfunction and cytotoxicity. We conclude that the prolonged, low-micromolar arsenite exposure paradigm resulting in mitoO 2  -. formation is necessary to affect Ca 2+ homeostasis and accumulate the cation in mitochondria. The arsenite requirements to promote mitoO 2  -. formation in the presence of sufficient mitochondrial Ca 2+ were instead remarkably lower in terms of both concentration and time of exposure. These conditions were associated with the induction of extensive DNA strand scission in the absence of detectable signs of toxicity. SIGNIFICANCE STATEMENT: In respiration-proficient cells, arsenite causes mitochondrial Ca 2+ accumulation and Ca 2+ -dependent mitochondrial superoxide formation. We now report that the second event requires remarkably lower concentrations of and time of exposure to the metalloid than the former. Indeed, a brief exposure to nanomolar levels of arsenite produced maximal effects under conditions in which the mitochondrial Ca 2+ concentration ([Ca 2+ ] m) was increased by inositol-1,4,5-trisphosphate receptor or ryanodine receptor agonists. Hence, specific substances or conditions enhancing the [Ca 2+ ] m may potentiate the deleterious effects of arsenite by selectively increasing mitochondrial superoxide formation.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

Arsenite-Induced Mitochondrial Superoxide Formation: Time and Concentration Requirements for the Effects of the Metalloid on the Endoplasmic Reticulum and Mitochondria