The Mitochondrial Voltage-Dependent Anion Channel 1, Ca Transport, Apoptosis, and Their Regulation.

In the outer mitochondrial membrane, the voltage-dependent anion channel 1 (VDAC1) functions in cellular Ca homeostasis by mediating the transport of Ca in and out of mitochondria. VDAC1 is highly Ca-permeable and modulates Ca access to the mitochondrial intermembrane space. Intramitochondrial Ca controls energy metabolism by enhancing the rate of NADH production modulating critical enzymes in the tricarboxylic acid cycle and fatty acid oxidation. Mitochondrial [Ca] is regarded as an important determinant of cell sensitivity to apoptotic stimuli and was proposed to act as a "priming signal," sensitizing the organelle and promoting the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca ([Ca]) mediates apoptosis is not known. Here, we review the roles of VDAC1 in mitochondrial Ca homeostasis and in apoptosis. Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca] and that this, in turn, augments VDAC1 expression levels. Thus, a new concept of how increased [Ca] activates apoptosis is postulated. Specifically, increased [Ca] enhances VDAC1 expression levels, followed by VDAC1 oligomerization, cytochrome release, and subsequently apoptosis. Evidence supporting this new model suggesting that upregulation of VDAC1 expression constitutes a major mechanism by which apoptotic stimuli induce apoptosis with VDAC1 oligomerization being a molecular focal point in apoptosis regulation is presented. A new proposed mechanism of pro-apoptotic drug action, namely Ca-dependent enhancement of VDAC1 expression, provides a platform for developing a new class of anticancer drugs modulating VDAC1 levels the promoter and for overcoming the resistance of cancer cells to chemotherapy.