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

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.

Figures (3)

Fig. 1 Fractions of total numbers of cells showing oxidation of cardiolipin, indicative of mitochondrial ROS levels, as assayed with the aid of NAO in A172 glioma cells that were treated for 24 h with 30 uM ErPC3 and/or PK 11195 at various concentrations. White columns indicate cells treated with PK 11195. Black columns indicate cells co-treated with PK 11195 and ErPC3. (n=9 per group); ###p< 0.001, for ErPC3 treatment only vs. untreated control; ***p<0.001, for ErPC3 plus PK 11195 treatments vs. ErPC3 treatment only

Fig. 1 Fractions of total numbers of cells showing oxidation of cardiolipin, indicative of mitochondrial ROS levels, as assayed with the aid of NAO in A172 glioma cells that were treated for 24 h with 30 uM ErPC3 and/or PK 11195 at various concentrations. White columns indicate cells treated with PK 11195. Black columns indicate cells co-treated with PK 11195 and ErPC3. (n=9 per group); ###p< 0.001, for ErPC3 treatment only vs. untreated control; ***p<0.001, for ErPC3 plus PK 11195 treatments vs. ErPC3 treatment only

Fig. 2 TSPO and VDAC driven initiation of the mitochondrial apoptosis pathway. A In this presentation, when not activated, TSPO and VDAC are not conducive for cytochrome c release. B Activation of TSPO (for example by ErPC3) leads to ROS generation, resulting in release of cytochrome c from cardiolipins at the inner mitochondrial membrane and formation of a pore via activation of the VDAC, allowing cytochrome c to enter the cytosol. C Application of TSPO ligands blocking TSPO activity, indicated as “inhibitors” in the figure (or TSPO knockdown) inhibits this ROS generation, restoring TSPO and VDAC to their inactive states

Fig. 2 TSPO and VDAC driven initiation of the mitochondrial apoptosis pathway. A In this presentation, when not activated, TSPO and VDAC are not conducive for cytochrome c release. B Activation of TSPO (for example by ErPC3) leads to ROS generation, resulting in release of cytochrome c from cardiolipins at the inner mitochondrial membrane and formation of a pore via activation of the VDAC, allowing cytochrome c to enter the cytosol. C Application of TSPO ligands blocking TSPO activity, indicated as “inhibitors” in the figure (or TSPO knockdown) inhibits this ROS generation, restoring TSPO and VDAC to their inactive states

Fig. 3 Diagram of cytochrome c release due to ROS generation following activation of TSPO and subsequent initiation of the mitochondrial apoptosis pathway mitochondrial swelling or loss of the AW,,. In other studies it was also found that ROS induced alterations of VDAC and/or ANT can induce mitochondrial membrane perme- ability selective for cytochrome c release, without causing further mitochondrial damage (Madesh and Hajnoczky 2001; Le Bras et al. 2005). It has been suggested that increase of VDAC pore size, for example via phosphory- lation by protein kinase A, can be a mechanism of allowing cytochrome c release (Banerjee and Ghosh 2006). It has also been suggested that assemblage of VDAC molecules into groups of up to 20 or even larger aggregates, including hexagonal packing, may play a role in cytochrome c release (Goncalves et al. 2007). ROS induced upregulation of the VDAC as a cytochrome c releasing channel can be prevented by the ROS chelator, epigallocatechin (EGCG; Jung et al. 2007). In this process of cytochrome c release from the mitochondria as an initiating step of the mitochondrial apoptosis pathway, interactions between ROS and VDAC, as well as ROS and cardiolipins, have come to be recognized to play central roles (Nomura et al. IONN0: Madech and Hainoczkv 2001: Nishimura et al 2001:

Fig. 3 Diagram of cytochrome c release due to ROS generation following activation of TSPO and subsequent initiation of the mitochondrial apoptosis pathway mitochondrial swelling or loss of the AW,,. In other studies it was also found that ROS induced alterations of VDAC and/or ANT can induce mitochondrial membrane perme- ability selective for cytochrome c release, without causing further mitochondrial damage (Madesh and Hajnoczky 2001; Le Bras et al. 2005). It has been suggested that increase of VDAC pore size, for example via phosphory- lation by protein kinase A, can be a mechanism of allowing cytochrome c release (Banerjee and Ghosh 2006). It has also been suggested that assemblage of VDAC molecules into groups of up to 20 or even larger aggregates, including hexagonal packing, may play a role in cytochrome c release (Goncalves et al. 2007). ROS induced upregulation of the VDAC as a cytochrome c releasing channel can be prevented by the ROS chelator, epigallocatechin (EGCG; Jung et al. 2007). In this process of cytochrome c release from the mitochondria as an initiating step of the mitochondrial apoptosis pathway, interactions between ROS and VDAC, as well as ROS and cardiolipins, have come to be recognized to play central roles (Nomura et al. IONN0: Madech and Hainoczkv 2001: Nishimura et al 2001:

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