VDAC activation by the 18 kDa translocator protein (TSPO), implications for apoptosis

Abstract

The voltage dependent anion channel (VDAC), located in the outer mitochondrial membrane, functions as a major channel allowing passage of small molecules and ions between the mitochondrial inter-membrane space and cytoplasm. Together with the adenine nucleotide translocator (ANT), which is located in the inner mitochondrial membrane, the VDAC is considered to form the core of a mitochondrial multiprotein complex, named the mitochondrial permeability transition pore (MPTP). Both VDAC and ANT appear to take part in activation of the mitochondrial apoptosis pathway. Other proteins also appear to be associated with the MPTP, for example, the 18 kDa mitochondrial Translocator Protein (TSPO), Bcl-2, hexokinase, cyclophylin D, and others. Interactions between VDAC and TSPO are considered to play a role in apoptotic cell death. As a consequence, due to its apoptotic functions, the TSPO has become a target for drug development directed to find treatments for neurodegenerative diseases and cancer. In this context, TSPO appears to be involved in the generation of reactive oxygen species (ROS). This generation of ROS may provide a link between activation of TSPO and of VDAC, to induce activation of the mitochondrial apoptosis pathway. ROS are known to be able to release cytochrome c from cardiolipins located at the inner mitochondrial membrane. In addition, ROS appear to be able to activate VDAC and allow VDAC mediated release of cytochrome c into the cytosol. Release of cytochrome c from the mitochondria forms the initiating step for activation of the mitochondrial apoptosis pathway. These data provide an understanding regarding the mechanisms whereby VDAC and TSPO may serve as targets to modulate apoptotic rates. This has implications for drug design to treat diseases such as neurodegeneration and cancer.

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

“…20, 21 We here demonstrate that when the ratio of TSPO to VDAC1 increases, mitochondrial production of ATP is limited and ROS levels are increased (Fig. 6), evidence that is consistent with previous publications.…”

“…6), evidence that is consistent with previous publications. 10,20,21 By influencing the cellular redox system, TSPO blocks the ubiquitination of mitochondrial proteins, essential for effective recruitment of the autophagosomal machinery via SQSTM1. 52 Cells largely devoid of TSPO show indeed an upregulation of mitochondrial ubiquitination with the same being observed in PRKCE ¡/¡ MEFs (Fig.…”

“…10 A role for TSPO in the execution of apoptosis has long been proposed and its natural and synthetic ligands i) endozepine, 11,12 ii) PK11195 [13][14][15][16] and iii) Ro-54864 17 are widely exploited as chemotherapy co-adjuvants. Other functions linked to TSPO include: i) the regulation of mitochondrial ATP production, 18,19 ii) the generation of reactive oxygen species, 20,21 and iii) the modulation of Ca 2C signaling. 22,23 Notably, its precise role in cell physiology has received relatively little attention, leaving its contribution to mitochondrial function largely illdefined.…”

“…5D). 56 However, knowing that an imbalance in the cellular redox state associates with a limitation of PARK2-mediated ubiquitination 57 and hypothesizing that TSPO may influence this pathway as its upregulation is linked to increased ROS production, 21 we investigated whether an antioxidant treatment could counteract the effects on ubiquitination in TSPO-overexpressing cells. And, by using the antioxidant SOD mimicking agent, MnTBAB, 44 the efficient ubiquitination of mitochondrial proteins was restored in TSPO-overexpressing cells (0.125 § 0.034) compared to untreated CTSPO cells (0.015 § 0.002) (Fig.…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…Cyclophilin D is the target of Cyclosporin A, a blocker of calcium-induced mitochondrial permeability transition. 83,84 Decreased growth factor signaling through Akt with resulting increased GSK3␤ activation leads to dissociation of hexokinase from VDAC and increased probability of mitochondrial permeability transition and apoptosis, and it can also increase sensitivity to chemotherapeutic agents. 85 Microtubule-targeted chemotherapeutic agents also favor mitochondrial permeability pore transition by modulating tubulin-VDAC interaction, 86 and some HAARTs may affect the mPTP by binding to ANT.…”