VDAC activation by the 18 kDa translocator protein (TSPO), implications for apoptosis (original) (raw)
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VDAC, a multi-functional mitochondrial protein as a pharmacological target
Regulation of mitochondrial physiology requires an efficient exchange of molecules between mitochondria and the cytoplasm via the outer mitochondrial membrane (OMM). The voltage-dependent anion channel (VDAC) lies in the OMM and forms a common pathway for the exchange of metabolites between the mitochondria and the cytosol, thus playing a crucial role in the regulation of metabolic and energetic functions of mitochondria. VDAC is also recognized to function in mitochondria-mediated apoptosis and in apoptosis regulation via interaction with anti-apoptotic proteins, namely members of Bcl-2 family, and the pro-survival protein, hexokinase, overexpressed in many cancer types. Thus, VDAC appears to be a convergence point for a variety of cell survival and cell death signals, mediated by its association with various ligands and proteins. In this article, we review mammalian VDAC, specifically focusing on VDAC1, addressing its functions in cell life and the regulation of apoptosis and its involvement in several diseases. Additionally, we provide insight into the potential of VDAC1 as a rational target for novel therapeutics.
VDAC1 as a player in mitochondria-mediated apoptosis and target for modulating apoptosis
Current medicinal chemistry, 2017
The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane protein, functions as a mitochondrial governor, controlling transport of metabolites in and out of the mitochondria and energy production, while also coordinating glycolysis and oxidative phosphorylation (OXPHOS). . VDAC1 plays a key role in mitochondria-mediated apoptosis by functioning in the release of apoptotic proteins located in the inter-membranal space (IMS) and due to its association with pro- and anti-apoptotic proteins. Thus, VDAC1 is considered as a promising target for controlling apoptosis. This review provides insight into the central role of VDAC1 in mammalian cell life and death and emphasizes VDAC1 function in apoptosis, focusing on VDAC1 oligomerization as an important step in the intrinsic apoptosis pathway involving mitochondria. Accumulated evidence suggests that VDAC1 oligomerization leads to the formation of a large pore that allows the passage of proteins, like cytochrome c (Cyto c...
The Journal of Cell Biology, 2001
Enhanced formation of reactive oxygen species (ROS), superoxide (O2·−), and hydrogen peroxide (H2O2) may result in either apoptosis or other forms of cell death. Here, we studied the mechanisms underlying activation of the apoptotic machinery by ROS. Exposure of permeabilized HepG2 cells to O2·− elicited rapid and massive cytochrome c release (CCR), whereas H2O2 failed to induce any release. Both O2·− and H2O2 promoted activation of the mitochondrial permeability transition pore by Ca2+, but Ca2+-dependent pore opening was not required for O2·−-induced CCR. Furthermore, O2·− alone evoked CCR without damage of the inner mitochondrial membrane barrier, as mitochondrial membrane potential was sustained in the presence of extramitochondrial ATP. Strikingly, pretreatment of the cells with drugs or an antibody, which block the voltage-dependent anion channel (VDAC), prevented O2·−-induced CCR. Furthermore, VDAC-reconstituted liposomes permeated cytochrome c after O2·− exposure, and this r...
Cellular oncology : the official journal of the International Society for Cellular Oncology, 2008
We have previously shown that the anti-neoplastic agent erucylphosphohomocholine (ErPC3) requires the mitochondrial 18 kDa Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), to induce cell death via the mitochondrial apoptosis pathway. With the aid of the dye JC-1 and cyclosporin A, applied to glioblastoma cells, we now investigated the significance of opening of the mitochondrial permeability transition pore (MPTP) for ErPC3-induced apoptosis in interaction with the TSPO ligands, PK 11195 and Ro5 4864. Furthermore, we measured cytochrome c release, and caspase-9 and -3 activation in this paradigm. The human glioblastoma cell lines, U87MG, A172 and U118MG express the MPTP-associated TSPO, voltage-dependent anion channel and adenine nucleotide transporter. Indeed, ErPC3-induced apoptosis was inhibited by the MPTP blocker cyclosporin A and by PK 11195 and Ro5 4864 in a concentration-dependent manner. Furthermore, PK 11195 and Ro5 4864 inh...
VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation
Cancer metabolism is emerging as a chemotherapeutic target. Enhanced glycolysis and suppression of mitochondrial metabolism characterize the Warburg phenotype in cancer cells. The flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol occur through voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane. Catabolism of respiratory substrates in the Krebs cycle generates NADH and FADH 2 that enter the electron transport chain (ETC) to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The ETC is also the major cellular source 41 of mitochondrial reactive oxygen species (ROS). αβ-Tubulin heterodimers decrease VDAC conductance in lipid bilayers. High constitutive levels of cytosolic free tubulin in intact cancer cells close VDAC decreasing mitochondrial ΔΨ and mitochondrial metabolism. The VDAC-tubulin interaction regulates VDAC opening and globally controls mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a VDAC-binding molecule lethal to some cancer cell types, and erastin-like compounds identified in a high-throughput screening antagonize the inhibitory effect of tubulin on VDAC. Reversal of tubulin inhibition of VDAC increases VDAC conductance and the flux of metabolites into and out of mitochondria. VDAC opening promotes a higher mitochondrial ΔΨ and a global increase in mitochondrial metabolism leading to high cytosolic ATP/ADP ratios that inhibit glycolysis. VDAC opening also increases ROS production causing oxidative stress that, in turn, leads to mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of the VDAC-tubulin interaction promotes cell death by a "double-hit model" characterized by reversion of the proproliferative Warburg phenotype (anti-Warburg) and promotion of oxidative stress.
VDAC, a multi-functional mitochondrial protein regulating cell life and death
Molecular Aspects of Medicine, 2010
Research over the past decade has extended the prevailing view of the mitochondrion to include functions well beyond the generation of cellular energy. It is now recognized that mitochondria play a crucial role in cell signaling events, inter-organellar communication, aging, cell proliferation, diseases and cell death. Thus, mitochondria play a central role in the regulation of apoptosis (programmed cell death) and serve as the venue for cellular decisions leading to cell life or death. One of the mitochondrial proteins controlling cell life and death is the voltage-dependent anion channel (VDAC), also known as mitochondrial porin. VDAC, located in the mitochondrial outer membrane, functions as gatekeeper for the entry and exit of mitochondrial metabolites, thereby controlling cross-talk between mitochondria and the rest of the cell. VDAC is also a key player in mitochondria-mediated apoptosis. Thus, in addition to regulating the metabolic and energetic functions of mitochondria, VDAC appears to be a convergence point for a variety of cell survival and cell death signals mediated by its association with various ligands and proteins. In this article, we review what is known about the VDAC channel in terms of its structure, relevance to ATP rationing, Ca 2+ homeostasis, protection against oxidative stress, regulation of apoptosis, involvement in several diseases and its role in the action of different drugs. In light of our recent findings and the recently solved NMR-and crystallography-based 3D structures of VDAC1, the focus of this review will be on the central role of VDAC in cell life and death, addressing VDAC function in the regulation of mitochondria-mediated apoptosis with an emphasis on structure-function relations. Understanding structure-function relationships of VDAC is critical for deciphering how this channel can perform such a variety of functions, all important for cell life and death. This review also provides insight into the potential of VDAC1 as a rational target for new therapeutics.
Reactive oxygen species and the mitochondrial signaling pathway of cell death
Histology and histopathology
Reactive oxygen species (ROS) are produced as a by-product of cellular metabolic pathways and function as a critical second messenger in a variety of intracellular signaling pathways. Thus, a defect or deficiency in the anti-oxidant defense system on the one hand and/or the excessive intracellular generation of ROS on the other renders a cell oxidatively stressed. As a consequence, direct or indirect involvement of ROS in numerous diseases has been documented. In most of these cases, the deleterious effect of ROS is a function of activation of intracellular cell-death circuitry. To that end, involvement of ROS at different phases of the apoptotic pathway, such as induction of mitochondrial permeability transition and release of mitochondrial death amplification factors, activation of intracellular caspases and DNA damage, has been clearly established. For instance, the ROS-induced alteration of constitutive mitochondrial proteins, such as the voltage-dependent anion channel (VDAC) a...
The Mitochondrial Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and Their Regulation
Frontiers in Oncology, 2017
In the outer mitochondrial membrane, the voltage-dependent anion channel 1 (VDAC1) functions in cellular Ca 2+ homeostasis by mediating the transport of Ca 2+ in and out of mitochondria. VDAC1 is highly Ca 2+-permeable and modulates Ca 2+ access to the mitochondrial intermembrane space. Intramitochondrial Ca 2+ controls energy metabolism by enhancing the rate of NADH production via modulating critical enzymes in the tricarboxylic acid cycle and fatty acid oxidation. Mitochondrial [Ca 2+ ] 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 2+ ([Ca 2+ ]i) mediates apoptosis is not known. Here, we review the roles of VDAC1 in mitochondrial Ca 2+ homeostasis and in apoptosis. Accumulated evidence shows that apoptosis-inducing agents act by increasing [Ca 2+ ]i and that this, in turn, augments VDAC1 expression levels. Thus, a new concept of how increased [Ca 2+ ]i activates apoptosis is postulated. Specifically, increased [Ca 2+ ]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 Ca 2+-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.
Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death
Nature Cell Biology, 2007
Voltage-dependent anion channels (VDACs) have been implicated as essential mediators of mitochondrial-dependent cell death by functioning as a channel-forming unit within the mitochondrial permeability transition (MPT) pore and the target of Bcl-2 family members. Here we report the effects of deletion of the 3 mammalian Vdac genes on mitochondrial-dependent cell death. Mitochondria from Vdac1-, Vdac3-, and Vdac1/Vdac3-null mice exhibited a Ca 2+ and oxidative stress-induced MPT that was indistinguishable from wildtype mitochondria. Similarly, Ca 2+ and oxidative-stress-induced MPT and cell death was unaltered or even exacerbated in fibroblasts lacking VDAC1, VDAC2, VDAC3, VDAC1/3, and VDAC1/2/3. Wildtype and Vdac-deficient mitochondria and cells also exhibited equivalent cytochrome c release, caspase cleavage, and cell death in response to Bax and Bid activation. These results indicate that VDACs are dispensable for both MPT and Bcl-2 family member-driven cell death. Mitochondria are intracellular organelles that mediate high-energy phosphate production, fatty acid metabolism, porphyrin synthesis, ion homeostasis and apoptotic and necrotic cell death. Apoptotic cell death is mediated by both the "extrinsic" pathway; consisting of death receptor signaling constituents, as well as the "intrinsic" pathway; consisting of pro-death Bcl-2 family members functioning at the level of the mitochondria and endoplasmic reticulum (1). Mitochondria are also critically involved in necrotic cell death following Ca 2+ overload, hypoxia, and oxidative damage, leading to swollen or ruptured mitochondria. The MPT pore, a protein complex that spans both the outer and inner mitochondrial membranes, is considered the mediator of this event and has been hypothesized to minimally consist of the VDAC in the outer membrane, the adenine nucleotide translocase (ANT) in the inner membrane, and cyclophilin-D in the matrix (2-4). The VDAC is comprised of a family of evolutionarily conserved ion channels that are the most abundant proteins in the outer mitochondrial membrane. The physiologic function of VDACs is to control the movement of adenine nucleotides, NADH, and other metabolites across the outer membrane (5,6). However, VDACs have also been proposed to possess a pathological function as mediators of mitochondrial-dependent cell death through formation of the permeability pore (7,8). In addition, VDACs have been proposed to be essential binding partners for pro-apoptotic Bcl-2 family members (9-12), combining to form protein-permeable