Essential Role of Voltage-Dependent Anion Channel in Various Forms of Apoptosis in Mammalian Cells

Abstract

Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic members of the Bcl-2 family such as Bax and Bak induce apoptogenic cytochrome c release in isolated mitochondria, whereas BH3-only proteins such as Bid and Bik do not directly target the VDAC to induce cytochrome c release. To investigate the biological significance of the VDAC for apoptosis in mammalian cells, we produced two kinds of anti-VDAC antibodies that inhibited VDAC activity. In isolated mitochondria, these antibodies prevented Bax-induced cytochrome c release and loss of the mitochondrial membrane potential (Δψ), but not Bid-induced cytochrome c release. When microinjected into cells, these anti-VDAC antibodies, but not control antibodies, also prevented Bax-induced cytochrome c release and apoptosis, whereas the antibodies did not prevent Bid-induced apoptosis, indicating that the VDAC is essential for Bax-induced, but not Bid-induced, apoptogenic mitochondrial changes and apoptotic cell death. In addition, microinjection of these anti-VDAC antibodies significantly inhibited etoposide-, paclitaxel-, and staurosporine-induced apoptosis. Furthermore, we used these antibodies to show that Bax- and Bak-induced lysis of red blood cells was also mediated by the VDAC on plasma membrane. Taken together, our data provide evidence that the VDAC plays an essential role in apoptogenic cytochrome c release and apoptosis in mammalian cells.

Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death

“…Previous work has suggested that VDAC2 would act as an endogenous inhibitor of Bak (but not Bax) (Cheng et al, 2003), whereas other VDAC isoforms would cooperate with Bax to promote apoptosis (Shimizu et al, 1999(Shimizu et al, , 2000a(Shimizu et al, , 2001. Our results point to a role for VDAC1 as an activator of Bax (but not Bak).…”

“…Although several studies have insisted on the fact that Bax/Bak-mediated MMP and PTPC-dependent MMP would occur in a completely independent, mechanistically distinct fashion, other reports suggest that proteins from the Bcl-2 family can functionally and physically interact with the PTPC (Marzo et al, 1998;Brenner et al, 2000;Belzacq et al, 2002). In this context, it has been suggested that VDAC2 would exert antiapoptotic functions by sequestering Bak (Cheng et al, 2003;Chandra et al, 2005) whereas other VDAC isoforms (possibly VDAC1 and VDAC3) would interact cooperatively with Bax to induce apoptosis (Shimizu et al, 1999(Shimizu et al, , 2001. Recently, one study performed on genetically manipulated mouse cells purported that none of the VDAC isoforms would be required for apoptotic MMP (Baines et al, 2007;.…”

hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria

“…42 The oligomerized Bax and Bak may form a pore for apoptogenic proteins, or may interact with the mitochondrial outer membrane voltagedependent anion channel (VDAC) to induce a change of VDAC permeability to allow apoptogenic proteins to pass through. 43 However, the mechanism of Bax-induced cytochrome c release from the mitochondria is not fully understood.…”

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

“…The regulatory action of BAX on VDAC is further demonstrated by the use of a VDAC-disrupted yeast strain that shows no Cyt c release upon BAX expression [20,24]. Furthermore BAX induced Cyt c release can be blocked by specific anti-VDAC antibodies [25], or by a VDAC inhibitor [26]. Interestingly, it was reported that tBID does not have an effect on the function of VDAC [27].…”