VDACs are MOM's ruin: Mitochondrial DNA (mtDNA) is normally kept within the mitochondria. It can be released into the cytosol in response to stress and thus encounter cytosolic DNA sensors, triggering type I interferon responses. During apoptosis, mtDNA release is mediated by macropores in the mitochondrial outer membrane (MOM) created by oligomerization of the proteins BAX and BAK. Kim et al. found that during oxidative stress, mtDNA escapes instead through macropores formed by oligomerization of voltage-dependent anion channels (VDACs) (see the Perspective by Crow). In a mouse model of lupus, an inhibitor of VDAC oligomerization diminished mtDNA release and downstream signaling events. This treatment reduced lupus-like symptoms in the model, suggesting a potential therapeutic route for conditions mediated by mtDNA release. Science , this issue p. 1531 ; see also p. 1445

Accumulating evidence implicates that the voltage-dependent anion channel (VDAC) functions in mitochondrion-mediated apoptosis and as a critical player in the release of apoptogenic proteins, such as cytochrome c, triggering caspase activation and apoptosis. The mechanisms regulating cytochrome c release and the molecular architecture of the cytochrome c-conducting channel remain unknown. Here the relationship between VDAC oligomerization and the induction of apoptosis was examined. We demonstrated that apoptosis induction by various stimuli was accompanied by highly increased VDAC oligomerization, as revealed by cross-linking and directly monitored in living cells using bioluminescence resonance energy transfer technology. VDAC oligomerization was induced in all cell types and with all apoptosis inducers used, including staurosporine, curcumin, As(2)O(3), etoposide, cisplatin, selenite, tumor necrosis factor alpha (TNF-α), H(2)O(2), and UV irradiation, all acting through different mechanisms yet all involving mitochondria. Moreover, correlation between the levels of VDAC oligomerization and apoptosis was observed. Furthermore, the apoptosis inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited VDAC oligomerization. Finally, a caspase inhibitor had no effect on VDAC oligomerization and cytochrome c release. We propose that VDAC oligomerization is involved in mitochondrion-mediated apoptosis and may represent a general mechanism common to numerous apoptogens acting via different initiating cascades. Thus, targeting the oligomeric status of VDAC, and hence apoptosis, offers a therapeutic strategy for combating cancers and neurodegenerative diseases.

Research over the last decade has extended the prevailing view of mitochondria to include functions well beyond the critical bioenergetics role in supplying ATP. It is now recognized that mitochondria play a crucial role in cell signaling events, inter-organelle communication, aging, many diseases, cell proliferation and cell death. Apoptotic signal transmission to the mitochondria results in the efflux of a number of potential apoptotic regulators to the cytosol that trigger caspase activation and lead to cell destruction. Accumulating evidence indicates that the voltagedependent anion channel (VDAC) is involved in this release of proteins via the outer mitochondrial membrane. VDAC in the outer mitochondrial membrane is in a crucial position in the cell, forming the main interface between the mitochondrial and the cellular metabolisms. VDAC has been recognized as a key protein in mitochondria-mediated apoptosis since it is the proposed target for the pro- and anti-apoptotic Bcl2-family of proteins and due to its function in the release of apoptotic proteins located in the inter-membranal space. The diameter of the VDAC pore is only about 2.6-3 nm, which is insufficient for passage of a folded protein like cytochrome c. New work suggests pore formation by homooligomers of VDAC or hetero-oligomers composed of VDAC and pro-apoptotic proteins such as Bax or Bak. This review provides insights into the central role of VDAC in cell life and death and emphasizes its function in the regulation of mitochondria- mediated apoptosis and, thereby, its potential as a rational target for new therapeutics.

The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.