The Mitochondrial Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and Their Regulation

Abstract

In the outer mitochondrial membrane, the voltage-dependent anion channel 1 (VDAC1) functions in cellular Ca²⁺ homeostasis by mediating the transport of Ca²⁺ in and out of mitochondria. VDAC1 is highly Ca²⁺-permeable and modulates Ca²⁺ access to the mitochondrial intermembrane space. Intramitochondrial Ca²⁺ controls energy metabolism by enhancing the rate of NADH production via modulating critical enzymes in the tricarboxylic acid cycle and fatty acid oxidation. Mitochondrial [Ca²⁺] 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 Ca²⁺ ([Ca²⁺]_i) mediates apoptosis is not known. Here, we review the roles of VDAC1 in mitochondrial Ca²⁺ homeostasis and in apoptosis. Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca²⁺]_i and that this, in turn, augments VDAC1 expression levels. Thus, a new concept of how increased [Ca²⁺]_i activates apoptosis is postulated. Specifically, increased [Ca²⁺]_i enhances VDAC1 expression levels, followed by VDAC1 oligomerization, cytochrome c 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 Ca²⁺-dependent enhancement of VDAC1 expression, provides a platform for developing a new class of anticancer drugs modulating VDAC1 levels via the promoter and for overcoming the resistance of cancer cells to chemotherapy.

Keywords: Ca2+ transporters; apoptosis; mitochondria; oligomerization; voltage-dependent anion channel.

Figure 1

Schematic representation of voltage-dependent anion channel 1 (VDAC1) as a multifunctional protein involved in Ca²⁺ and metabolite transport, energy production, and the structural and functional association of mitochondria with the endoplasmic reticulum (ER). The various functions of VDAC1 in cell and mitochondria functions are presented. These include (A) Ca²⁺ signaling by transporting Ca²⁺; (B) control of metabolic cross talk between the mitochondria and the rest of the cell; (C) mediating cellular energy production by transporting ATP/ADP, NADH, and acyl-CoA from the cytosol to the intermembrane space and regulating glycolysis via the association with hexokinase (HK); (D) involvement in structural and functional association with the ER, mediating Ca²⁺ transport from the ER to mitochondria; (E) participation in apoptosis via its oligomerization to form a protein-conducting channel within a VDAC1 homo-oligomer, allowing Cyto c release and apoptotic cell death. Ca²⁺ influx and efflux transport systems in the outer mitochondrial membrane (OMM) and IMM are shown. In the OMM, VDAC1 is presented as a Ca²⁺ channel and also functions in the transport of Mg²⁺. In the IMM, Ca²⁺ uptake into the matrix is mediated by a Ca²⁺-selective transporter, the mitochondrial Ca²⁺ uniporter (MCU), regulated by a calcium-sensing accessory subunit (MCU1). Ryanodine receptor (RyR) in the IMM mediates Ca²⁺ influx. Ca²⁺ efflux is mediated by NCLX, an Na⁺/Ca²⁺ exchanger. High levels of matrix Ca²⁺ accumulation trigger the opening of the PTP, a fast Ca²⁺ release channel. The function of Ca²⁺ in regulation of energy production is mediated via tricarboxylic acid (TCA) cycle regulation. This includes activation of pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH), and α-ketoglutarate dehydrogenase (αKGDH) by intramitochondrial Ca²⁺, leading to enhanced activity of the TCA cycle. The electron transport chain (ETC) and the ATP synthase (F_oF₁) are also presented. Molecular fluxes are indicated by arrows. VDAC1 mediates the transfer of fatty acid acyl-CoAs across the OMM to the IMS, where they are converted into acylcarnitine by CPT1a for further processing by β-oxidation. VDAC1 is involved in cholesterol transport by being constituent of a multi-protein complex, the transduceosome, containing Star/TSPO/VDAC1. The ER associated with the mitochondria is presented with key proteins indicated. These include the inositol 3 phosphate receptor type 3 (IP3R3), the sigma1 receptor (Sig1R) (a reticular chaperone), binding immunoglobulin protein (BiP), the ER heat shock protein (HSP70) chaperone, and glucose-regulated protein 75 (GRP75). IP3 activates the IP3R in the ER to release Ca²⁺ that is directly transferred to the mitochondrion via VDAC1.

Figure 2

Proposed model for apoptosis stimuli-induced increase in voltage-dependent anion channel 1 (VDAC1) expression levels leading to VDAC1 oligomerization, Cyto c release, and apoptosis and possible inhibition steps. A schematic model describing the novel pathway proposed for apoptosis induction involving elevation of [Ca²⁺]_i leading to VDAC1 overexpression. (A) This facilitates VDAC1 oligomerization to form a large channel mediating cytochrome c release from the mitochondrion into the cytosol, resulting in apoptosis activation. It is proposed that the overexpression of VDAC1 in diseases such as Alzheimer’s disease, cardiovascular diseases, and diabetes is associated mitochondrial dysfunction, including apoptosis induction (B).