Mitochondrial voltage-dependent

The Mitochondrial Voltage-Dependent Anion-Selective Channel... 

T. Rostovtseva, K. Sheldon, E. Hassanzadeh, C. Monge, V. Saks, S. Bezrukov, and D. Sackett, Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc. Natl. Acad. Sci. USA, 105 (2008) 18746-51. 

Figure 1.12 Second-generation antitumor drug candidates having novel chemo-types, which act on mitochondrial voltage-dependent anion channels.

Mitochondrial cytochrome c release is regulated by the Bcl-2 family of proteins (Tsujimoto and Shimizu 2000), which are targeted at the mitochondrial permeability transition pore (PTP) whose multisubunit protein complex includes the mitochondrial voltage-dependent anion channel. NO inhibits the opening of PTP. Thus, NO exposure results in significantly lower cytochrome c release for the same degree of PTP opening in apoptotic cells (Brookes et al. 2000). 

The PBRis distinct from the central BZ receptor although both can be present in the same tissues in differing ratios. PBRs are predominately localized on the outer mitochondrial membrane and are thus intracellular BZ recognition sites. The PBR is composed of three subunits an 18,000 mol wt subunit that binds isoquinoline carboxamide derivatives a 30,000 mol wt subunit that binds BZs and a 32,000 mol wt voltage-dependent anion channel subunit. The porphyrins may be endogenous ligands for the PBR. PBRs are involved in the control of cell proliferation and differentiation and steroidogenesis. 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

At the cellular level, chlordecone causes spontaneous neurotransmitter release (End et al. 1981) and increases in free intracellular calcium in synaptosomes (Bondy and Halsall 1988 Bondy and McKee 1990 Bondy et al. 1989 Komulainen and Bondy 1987). This appears to be due at least in part to increased permeability of the plasma membrane (Bondy and Halsall 1988 Bondy and McKee 1990 Bondy et al. 1989 Komulainen and Bondy 1987), activation of voltage-dependent calcium channels (Komulainen and Bondy 1987), and inhibition of brain mitochondrial calcium uptake (End et al. 1979, 1981). 

Figure 3. Possible mechanisms of actions of Bcl-2 members. Two prevailing models through which Bcl-2 membas trigger cytochrome c release have been suggested. In both models phospholipids in the bilayer stnicture either individually and/or collectively induce a conformational change in Bcl-2 members, allowing them to insert into the outer mitochondrial membrane. In model 1 proapoptotic proteins destabilize the outer mitochondrial membrane, oligomerize and form channels through which cytochrome c and other proteins of the intermembrane space can escape.BcI-2 proteins such as Bax or tBid act in concert with other proteins of the BcI-2 family to form channels. In model 2 Bcl-2 members such as Bax interact with residoit proteins in the outer membrane (OM) such as the voltage-dependent anion...

McEnery, M.W., Snowman, A.M., Trifiletti, R.R., and Snyder, S.H., 1992, Isolation ofthe mitochondrial benzodiazepine receptor association with the voltage-dependent anion channel and the adenine nucleotide carrier, Proc.Natl.Acad.Sci. U.S.A. 89 3170-3174. 

Germain, M., Mathai, J. P., and Shore, G. C., 2002, BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria, J. Biol. Chem. 277, pp. 18053—18060 Gincel, D., Zaid, H., and Shoshan-Barmatz, V., 2001, Calcium binding and translocation by the voltage-dependent anion channel a possible regulatory mechanism in mitochondrial function, Biochem. J. 358, pp. 147-155... 

Vander Heiden, M.G., Li, X. X., Gottlieb, E., Hill, R. B., Thompson, C. B., and Colombini, M., 2001, Bcl-XL promotes the open configuration of die voltage-dependent anion channel and metabolite passage through die outer mitochondrial membrane, J. Biol. Chem. 276, pp. 19414—19419... 

Shoshan-Barmatz V, Gincel D. The voltage-dependent anion channel characterization, modulation, and role in mitochondrial function in cell life and death. Cell Biochem Biophys. 2003 39 279-292. 

Figure 17.3. Permeability transition pore (PTP). The PTP consists of voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and several associated molecules including cyclophilin D (CypD) and peripheral benzodiazepine receptor (PBR). IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane CytC, cytochrome c.

The mitochondrial permeability transition (MPT) is the loss of the inner mitochondrial membrane impermeability to solutes caused by opening of the MPT pore (MPTP). In turn, this action results in a loss of mitochondrial function and provides a common mechanism implicated in activation of mi-tophagy/autophagy, apoptosis, and necrosis in different cell systems. Although the composition of MPTP is not fully settled, multiple studies suggest involvement of adenine nucleotide translocase (ANT) in the inner mitochondrial membrane, voltage-dependent anion channel (VDAC or porin) in the outer membrane, and cyclophilin D (CypD) in the matrix. 

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