Emerging molecular mechanisms in chemotherapy: Ca ²⁺ signaling at the mitochondria-associated endoplasmic reticulum membranes

Abstract

Inter-organellar communication often takes the form of Ca ²⁺ signals. These Ca ²⁺ signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca ²⁺ signals are the mitochondria. ER–mitochondrial Ca ²⁺ 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 ²⁺ concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca ²⁺ uptake. In the mitochondria, the Ca ²⁺ signal is decoded differentially depending on its spatiotemporal characteristics. While Ca ²⁺ oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca ²⁺ overload results in apoptosis. Many chemotherapeutics depend on efficient ER–mitochondrial Ca ²⁺ signaling to exert their function. However, several oncogenes and tumor suppressors present in the MAMs can alter Ca ²⁺ signaling in cancer cells, rendering chemotherapeutics ineffective. In this review, we will discuss recent studies that connect ER–mitochondrial Ca ²⁺ transfer, tumor suppressors and oncogenes at the MAMs, and chemotherapy.