Mitochondrial DNA might be influenced in calprotectin-induced cell death

Abstract

It is generally believed that calprotectin acts via exclusion of extracellular zinc, and/or binding of calprotectin to a cell membrane receptor, and consequently, activation of a signaling pathway for apoptosis. Recently, we suggested that calprotectin may have an “internal target” within cells. Here, using target theory, we provided evidence that this internal target is DNA. Trypan blue (TB) and dimythylthiazol diphenyl tetrazolium bromide (MTT) assays were used to estimate survival of calprotectin-treated cells. TB assay relies on the viability of cell membrane, while MTT assay relies on the functionality of mitochondria. We demonstrated that MTT-based survival values fit to the “single-hit, single-target” model, while TB-based survival values are best matched to the “single-hit, multi-target” model with N=2. Assumption of DNA as the target of calprotectin is fully consistent with the models, since each mitochondrion contains one chromosome and each “cell” is diploid and contains two chromosome sets. To the best of our knowledge this is the first report that suggests mitochondrial DNA is affected during calprotectin-induced cell death. Furthermore, our results explain why toxicity measures (like LD50), when estimated based on TB assay, are sometimes significantly greater than toxicity measures based on MTT assay.