VDAC1 functions in Ca²⁺ homeostasis and cell life and death in health and disease

In the outer mitochondrial membrane (OMM), the voltage-dependent anion channel 1 (VDAC1) serves as a mitochondrial gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell. VDAC1 also functions in cellular Ca²⁺ homeostasis by transporting Ca²⁺ in and out of mitochondria. VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, contributing to the release of apoptotic proteins located in the inter-membranal space (IMS) and regulating apoptosis via association with pro- and anti-apoptotic members of the Bcl-2 family of proteins and hexokinase. VDAC1 is highly Ca²⁺-permeable, transporting Ca²⁺ to the IMS and thus modulating Ca²⁺ access to Ca²⁺ transporters in the inner mitochondrial membrane. Intra-mitochondrial Ca²⁺ controls energy metabolism via modulating critical enzymes in the tricarboxylic acid cycle and in fatty acid oxidation. Ca²⁺ also determines cell sensitivity to apoptotic stimuli and promotes the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca²⁺ mediates apoptosis is not known. Here, the roles of VDAC1 in mitochondrial Ca²⁺ homeostasis are presented while emphasizing a new proposed mechanism for the mode of action of pro-apoptotic drugs. This view, proposing that Ca²⁺-dependent enhancement of VDAC1 expression levels is a major mechanism by which apoptotic stimuli induce apoptosis, position VDAC1 oligomerization at a molecular focal point in apoptosis regulation. The interactions of VDAC1 with many proteins involved in Ca²⁺ homeostasis or regulated by Ca²⁺, as well as VDAC-mediated control of cell life and death and the association of VDAC with disease, are also presented.