Bcl-2 family proteins are recognized as major regulators of the mitochondrial pathway of apoptosis. They control the mitochondrial outer membrane permeabilization (MOMP) by directly localizing to this organelle. Further investigations demonstrated that Bcl-2 related proteins are also found in other intracellular compartments such as the endoplasmic reticulum, the Golgi apparatus, the nucleus and the peroxisomes. At the level of these organelles, Bcl-2 family proteins not only regulate MOMP in a remote fashion but also participate in major cellular processes including calcium homeostasis, cell cycle control and cell migration. With the advances of live cell imaging techniques and the generation of fluorescent recombinant proteins, it became clear that the distribution of Bcl-2 proteins inside the cell is a dynamic process which is profoundly affected by changes in the cellular microenvironment. Here, we describe the current knowledge related to the subcellular distribution of the Bcl-2 family of proteins and further emphasize on the emerging concept that this highly dynamic process is critical for cell fate determination.

Bcl-2 family proteins are considered as one of the major regulators of apoptosis. Indeed, this family is known to control the mitochondrial outer membrane permeabilization (MOMP): a central step in the mitochondrial pathway of apoptosis. However, in recent years Bcl-2 family members began to emerge as a new class of intracellular calcium (Ca²⁺) regulators. At mitochondria-ER contacts (MERCs) these proteins are able to interact with major Ca²⁺ transporters, thus controlling mitochondrial Ca²⁺ homeostasis and downstream Ca²⁺ signalling pathways. Beyond the regulation of cell survival, this Bcl-2-dependent control over the mitochondrial Ca²⁺ dynamics has far-reaching consequences on the physiology of the cell. Here, we review how the Bcl-2 family of proteins mechanistically regulate mitochondrial Ca²⁺ homeostasis and how this regulation orchestrates cell death/survival decisions as well as the non-apoptotic process of cell migration.