Emerging molecular mechanisms in chemotherapy: Ca²⁺ signaling at the mitochondria-associated endoplasmic reticulum membranes

Inter-organellar communication often takes the form of Ca²⁺ signals. These Ca²⁺ signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca²⁺ signals are the mitochondria. ER-mitochondrial Ca²⁺ 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 Ca²⁺ concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca²⁺ uptake. In the mitochondria, the Ca²⁺ signal is decoded differentially depending on its spatiotemporal characteristics. While Ca²⁺ oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca²⁺ overload results in apoptosis. Many chemotherapeutics depend on efficient ER-mitochondrial Ca²⁺ signaling to exert their function. However, several oncogenes and tumor suppressors present in the MAMs can alter Ca²⁺ signaling in cancer cells, rendering chemotherapeutics ineffective. In this review, we will discuss recent studies that connect ER-mitochondrial Ca²⁺ transfer, tumor suppressors and oncogenes at the MAMs, and chemotherapy.