The Role of VDAC in Apoptosis
Apoptosis can be initiated by damaging mitochondria and inducing the
mitochondrial permeability transition. However, while this may be
sufficient to initiate the process, this is not a necessary condition.
Finucane et al. (1999) and Krohn et al., (1999) demonstrated cytochrome
c release from the intermembrane space and caspase activation without
depolarization of the inner membrane. Often inner membrane depolarization
follows cytochrome c release and the potential can be restored in permeabilized
cells by adding exogenous cytochrome c. Eventually, inner membrane
depolarization does occur, but this may be the result of degredative pathways
that lead to cellular fragmentation. Thus, changes in the inner
membrane may be secondary or subsequent to changes in the outer membrane
(unless the event initiating the apoptotic process specifically targeted
components of the inner membrane/matrix). Indeed, strong evidence
indicates that when IL-3 is removed from the medium of a cell line that
depends on this growth factor for growth and survival, prior to cytochrome
c release the permeability of the outer membrane to metabolites is actually
greatly reduced (Bialik et al., 1999; Vander Heiden et al., 1999).
It is this reduction in permeability that leads to changes that eventually
result in the release of the contents of the intermembrane space.
At this state, cells can be rescued by restoring IL-3 and thus reversing
the drop in outer membrane permeability and preventing progression to
apoptosis (Vander Heiden et al., 2000).
The reduction in metabolite permeability is likely the result of closure
of VDAC channels as these are the major permeability pathways through
the outer membrane. Different groups have reported that the anti-apoptotic
protein, Bcl-xL, can interact with and modulate the activity of VDAC channels
from the mitochondrial outer membrane. However, whether Bcl-xL promotes
the open or closed conformation of VDAC is a controversial issue.
Recent publications by the Tsujimoto laboratory (Shimizu et al., 1999,
2000) contradict those obtained in the Colombini and Thompson laboratories
(J. Biol. Chem. in press). The latter report that Bcl-xL promotes
the maintenance of VDAC in the open configuration. According to
these results, Bcl-xL exerts its protective role by restoring metabolic
exchange across the outer membrane without inducing the loss of intermembrane
space proteins such as cytochrome c.
Bialik, S., Cryns, V.L., Drincic, A., Miyata, S., Wollowick, A.L., Srinivasan,
A., and Kitsis, R.N. (1999). The mitochondrial apoptotic pathway is activated
by serum and glucose deprivation in cardiac myocytes. Circ. Res. 85(5):
Finucane, D.M., Waterhouse, N.J., Amarante-Mendes, G.P., Cotter, T.G.,
and Green, D.R. (1999). Collapse of the inner mitochondrial transmembrane
potential is not required for apoptosis of HL60 cells. Exp. Cell Res.
Krohn, A.J., Wahlbrink, T., and Prehn, J.H. (1999). Mitochondrial depolarization
is not required for neuronal apoptosis. J. Neurosci. 19(17): 7394-7404
Shimizu, S., Konishi, A., Kodama, T., and Tsujimoto, Y. (2000). BH4 domain
of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel
and inhibits apoptotic mitochondrial changes and cell death. Proc. Natl.
Acad. Sci. USA. 97: 3100-3105
Shimizu, S., Narita, M., and Tsujimoto, Y. (1999). Bcl-2 family proteins
regulate the release of apoptogenic cytochrome c by the mitochondrial
channel VDAC. Nature. 399: 483-487
Vander Heiden, M.G., Chandel, N.S., Schumacker, P.T., and Thompson, C.B.
(1999). Bcl-xL prevents cell death following growth factor withdrawal
by facilitating mitochondrial ATP/ADP exchange. Mol. Cell. 3(2): 159-167
Vander Heiden, M.G., Chandel, N.S., Li, X.X., Schumacker, P.T., Colombini,
M., and Thompson, C.B. (2000). Outer mitochondrial membrane permeability
can regulate coupled respiration and cell survival. Proc. Natl. Acad.
Sci. USA. 97: 4666-4671
Vander Heiden,M.G., Li, X.X. , Gottleib, E. , Hill, R.B., Thompson, C.B.,
and Colombini, M. 2001. Bcl-xL Promotes the Open Configuration of VDAC
and Metabolite Passage through the Mitochondrial Outer Membrane. Journal
of Biological Chemistry 276: 19414-9