Emerging molecular mechanisms in chemotherapy: Ca signaling at the mitochondria-associated endoplasmic reticulum membranes

Inter-organellar communication often takes the form of Ca signals. These Ca signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca signals are the mitochondria. ER-mitochondrial Ca transfer is possible through the existence of mitochondria-associated ER membranes (MAMs), ER structures that are in the proximity of the mitochondria. This creates a micro-domain in which the Ca concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca uptake. In the mitochondria, the Ca signal is decoded differentially depending on its spatiotemporal characteristics. While Ca oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca overload results in apoptosis. Many chemotherapeutics depend on efficient ER-mitochondrial Ca signaling to exert their function. However, several oncogenes and tumor suppressors present in the MAMs can alter Ca signaling in cancer cells, rendering chemotherapeutics ineffective. In this review, we will discuss recent studies that connect ER-mitochondrial Ca transfer, tumor suppressors and oncogenes at the MAMs, and chemotherapy.