Modulation of Ca Signaling by Anti-apoptotic B-Cell Lymphoma 2 Proteins at the Endoplasmic Reticulum-Mitochondrial Interface.

Mitochondria are important regulators of cell death and cell survival. Mitochondrial Ca levels are critically involved in both of these processes. On the one hand, excessive mitochondrial Ca leads to Ca-induced mitochondrial outer membrane permeabilization and thus apoptosis. On the other hand, mitochondria need Ca in order to efficiently fuel the tricarboxylic acid cycle and maintain adequate mitochondrial bioenergetics. For obtaining this Ca, the mitochondria are largely dependent on close contact sites with the endoplasmic reticulum (ER), the so-called mitochondria-associated ER membranes. There, the inositol 1,4,5-trisphosphate receptors are responsible for the Ca release from the ER. It comes as no surprise that this Ca release from the ER and the subsequent Ca uptake at the mitochondria are finely regulated. Cancer cells often modulate ER-Ca transfer to the mitochondria in order to promote cell survival and to inhibit cell death. Important regulators of these Ca signals and the onset of cancer are the B-cell lymphoma 2 (Bcl-2) family of proteins. An increasing number of reports highlight the ability of these Bcl-2-protein family members to finely regulate Ca transfer from ER to mitochondria both in healthy cells and in cancer. In this review, we focus on recent insights into the dynamic regulation of ER-mitochondrial Ca fluxes by Bcl-2-family members and how this impacts cell survival, cell death and mitochondrial energy production.