Ca2+-dependent mast cell death induced by Ag (I) via cardiolipin oxidation and ATP depletion

Abstract

In genetically susceptible humans and/or experimental animals, ions of heavy metals, Hg (II), Au (III), and Ag (I) have been shown to strongly induce autoimmunity, in which mast cells have been implicated to play a role. Here, we demonstrate that Ag (I) application results in mast cell death through a unique Ca(2+)- and mitochondria-dependent pathway. As cellular susceptibilities to Ag (I) cytotoxicity varied considerably, we analyzed the cell death pathway in the low and high responding cells. In the low responding cells, long application (e.g., 20 h) of Ag (I) at concentrations (>or=30 microM) induced cell death, which was accompanied by mitochondrial membrane depolarization, cyt c release, and caspase-3/7 activation but was not prevented by selective inhibitors of caspase-3/7 and the mitochondrial permeability transition. The cell death was preceded by elevations in the cytoplasmic and mitochondrial Ca(2+) levels, and Ca(2+) responses and cell death were prevented by thiol reagents, including DTT, N-acetylcysteine, and reduced glutathione monoethyl ester. In the high responding cells, Ag (I) evoked considerable cell death by necrosis within 1 h, without inducing caspase activation, and this cell death was reduced significantly by depleting extracellular but not intracellular Ca(2+). Moreover, Ag (I) strongly induced Ca(2+)-dependent CL oxidation and intracellular ATP depletion, both of which were blocked by thiol reagents. These results suggest that Ag (I) activates thiol-dependent Ca(2+) channels, thereby promoting Ca(2+)-dependent CL oxidation, cyt c release, and ATP depletion. This necrotic cell death may play roles in Ag-induced inflammation and autoimmune disorders.

Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor

“…Following exposure to AgNPs, and as quickly as 10 min, mast cells started to degranulate (Fig 1B) as evidenced by membrane blebbing and reduction in the number of granules present in the cells over time. It was previously shown that exposure to silver ions (Ag + ) induces mast cell apoptosis through cardiolipin oxidation and ATP depletion [30]. However, we assessed cellular toxicity in response to AgNPs (25 μg/ml) and found that 24 h exposure did not trigger any significant cell death (S1 Fig) suggesting a possible different mechanism between Ag + and AgNPs in mediating mast cell activation/toxicity.…”

Mitochondrial Oxidative Stress Is the General Reason for Apoptosis Induced by Different-Valence Heavy Metals in Cells and Mitochondria

“…Cell research. Ag + induced mitochondrial apoptosis in human Chang liver cells, Ewing's sarcoma A673 cells, A549 lung cancer cells, human airway smooth muscle, human breast SKBR3 cancer cells, histiocytic lymphoma U-937 cells, human promyelocytic HL-60 cells, human keratinocytes, CHO-K line cells, human bronchial epithelial BEAS-2B cells, human skin fibroblasts, and mouse AML12 hepatocytes [89][90][91][92][93][94][95][96][97][98][99][100][101][102]. The apoptosis manifested alongside decreased cell viability, caspase 3 and 7 activation, pro-apoptotic genes (Bax and Bcl-2) expression, increased metallothionein expression, ATP depletion, and DNA fragmentation.…”

Selective mitochondrial staining with small fluorescent probes: importance, design, synthesis, challenges and trends for new markers

“…These assays combined provide extensive information about mitochondrial distribution, fusion, fission, motility and calcium flux. [75][76][77] These dyes must be stored at 220 uC, in an anhydrous environment and protected from light, and their ester derivatives are susceptible to hydrolysis, particularly when found in solution. Another derivative is the known MitoRed, which notably has an ester function and must also be stored in the dark and frozen (2-8 uC).…”