Arsenite-Induced Mitochondrial Superoxide Formation: Time and Concentration Requirements for the Effects of the Metalloid on the Endoplasmic Reticulum and Mitochondria
| Autor: | Mara Fiorani, Liana Cerioni, Orazio Cantoni, Andrea Guidarelli, Alessia Catalani |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Time Factors Arsenites Mitochondrion calcium signaling reactive oxygen species (ROS) Endoplasmic Reticulum 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Superoxides oxidative stress Humans Receptor Metalloids Arsenite Pharmacology Dose-Response Relationship Drug U937 cell Superoxide Ryanodine receptor Endoplasmic reticulum genotoxicity U937 Cells Mitochondria Cell biology mitochondria cell death Teratogens 030104 developmental biology chemistry DNA damage ryanodine receptors superoxide Molecular Medicine Reactive Oxygen Species 030217 neurology & neurosurgery Homeostasis |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 373:62-71 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 (O2−.) formation. Under these conditions, we observe an initial Ca2+ mobilization from the ER associated with the mitochondrial accumulation of the cation, which is followed by Ca2+-dependent mitochondrial O2−. (mitoO2−.) 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 O2− formation in cells supplemented with inositol-1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR) agonists. Indeed, nanomolar arsenite induced maximal O2−. formation after only 10 minutes of exposure, and this response was uniquely dependent on the enforced mitochondrial Ca2+ accumulation. The dramatic anticipation of and sensitization to the effects of arsenite caused by the IP3R 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 mitoO2−. formation is necessary to affect Ca2+ homeostasis and accumulate the cation in mitochondria. The arsenite requirements to promote mitoO2−. formation in the presence of sufficient mitochondrial Ca2+ 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 Ca2+ accumulation and Ca2+-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 Ca2+ concentration ([Ca2+]m) was increased by inositol-1,4,5-trisphosphate receptor or ryanodine receptor agonists. Hence, specific substances or conditions enhancing the [Ca2+]m may potentiate the deleterious effects of arsenite by selectively increasing mitochondrial superoxide formation. |
| Databáze: | OpenAIRE |
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