Dynamic Control of Mitochondrial Ca(2+) Levels as a Survival Strategy of Cancer Cells

Cancer cells have increased energy requirements due to their enhanced proliferation activity. This energy demand is, among others, met by mitochondrial ATP production. Since the second messenger Ca(2+) maintains the activity of Krebs cycle dehydrogenases that fuel mitochondrial respiration, proper mitochondrial Ca(2+) uptake is crucial for a cancer cell survival. However, a mitochondrial Ca(2+) overload induces mitochondrial dysfunction and, ultimately, apoptotic cell death. Because of the vital importance of balancing mitochondrial Ca(2+) levels, a highly sophisticated machinery of multiple proteins manages mitochondrial Ca(2+) homeostasis. Notably, mitochondria sequester Ca(2+) preferentially at the interaction sites between mitochondria and the endoplasmic reticulum (ER), the largest internal Ca(2+) store, thus, pointing to mitochondrial-associated membranes (MAMs) as crucial hubs between cancer prosperity and cell death. To investigate potential regulatory mechanisms of the mitochondrial Ca(2+) uptake routes in cancer cells, we modulated mitochondria–ER tethering and the expression of UCP2 and analyzed mitochondrial Ca(2+) homeostasis under the various conditions. Hence, the expression of contributors to mitochondrial Ca(2+) regulation machinery was quantified by qRT-PCR. We further used data from The Cancer Genome Atlas (TCGA) to correlate these in vitro findings with expression patterns in human breast invasive cancer and human prostate adenocarcinoma. ER-mitochondrial linkage was found to support a mitochondrial Ca(2+) uptake route dependent on uncoupling protein 2 (UCP2) in cancer cells. Notably, combined overexpression of Rab32, a protein kinase A-anchoring protein fostering the ER-mitochondrial tethering, and UCP2 caused a significant drop in cancer cells' viability. Artificially enhanced ER-mitochondrial tethering further initiated a sudden decline in the expression of UCP2, probably as an adaptive response to avoid mitochondrial Ca(2+) overload. Besides, TCGA analysis revealed an inverse expression correlation between proteins stabilizing mitochondrial-ER linkage and UCP2 in tissues of human breast invasive cancer and prostate adenocarcinoma. Based on these results, we assume that cancer cells successfully manage mitochondrial Ca(2+) uptake to stimulate Ca(2+)-dependent mitochondrial metabolism while avoiding Ca(2+)-triggered cell death by fine-tuning ER-mitochondrial tethering and the expression of UCP2 in an inversed manner. Disruption of this equilibrium yields cancer cell death and may serve as a treatment strategy to specifically kill cancer cells.