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Review
. 2012 Jun;1818(6):1444-50.
doi: 10.1016/j.bbamem.2011.10.025. Epub 2011 Oct 28.

The role of VDAC in cell death: friend or foe?

Kyle S McCommis  1 , Christopher P Baines
Affiliations
Review

The role of VDAC in cell death: friend or foe?

Kyle S McCommis et al. Biochim Biophys Acta. 2012 Jun.

Abstract

As the voltage-dependent anion channel (VDAC) forms the interface between mitochondria and the cytosol, its importance in metabolism is well understood. However, research on VDAC's role in cell death is a rapidly growing field, unfortunately with much confusing and contradictory results. The fact that VDAC plays a role in outer mitochondrial membrane permeabilization is undeniable, however, the mechanisms behind this remain very poorly understood. In this review, we will summarize the studies that show evidence of VDAC playing a role in cell death. To begin, we will discuss the evidence for and against VDAC's involvement in mitochondrial permeability transition (MPT) and attempt to clarify that VDAC is not an essential component of the MPT pore (MPTP). Next, we will evaluate the remaining literature on VDAC in cell death which can be divided into three models: proapoptotic agents escaping through VDAC, VDAC homo- or hetero-oligomerization, or VDAC closure resulting in outer mitochondrial membrane permeabilization through an unknown pathway. We will then discuss the growing list of modulators of VDAC activity that have been associated with induction/protection against cell death. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.

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Figures

Fig. 1
Fig. 1. Proposed models for VDAC’s role in outer mitochondrial membrane permeabilization and induction of apoptosis
In model #1, the VDAC is a component of the MPTP and therefore causes cytochrome c release indirectly through the swelling and rupture of mitochondria. This model has largely been discredited, as mitochondria lacking VDACs still possess a normal MPT response. Model #2 involves either homo-oligomerization of VDAC channels or hetero-oligomerization with VDAC and Bax/Bak to produce a large channel capable of releasing cytochrome c. However, this model is also highly questionable as cells devoid of all VDACs actually exhibit enhanced cell death in response to apoptotic stimuli, thus suggesting that VDAC plays a protective role against cell death. Evidence of VDAC’s interaction with Bax or Bak is limited and has also been questioned. Model #3 details how anti-apoptotic agents modulate VDAC to keep it in the open state, maintaining adenine nucleotide flux, thus maintaining outer membrane permeability. On the other hand, a growing list of pro-apoptotic modulators of VDAC have been shown to close VDAC, inhibiting adenine nucleotide flux, causing mitochondrial permeability and cell death. This model #3 thus fits with concept of a functional VDAC channel being cytoprotective.
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