VDAC-2: Mitochondrial outer membrane regulator masquerading as a channel?

Abstract

The voltage-dependent anion channels (VDACs) are the workforce of mitochondrial transport and as such are required for cellular metabolism. The elaborate interplay between mitochondria and the apoptotic pathway supports a role for VDACs as a major regulator of cell death. Although VDAC-1 has an established role in apoptosis and cell homeostasis, the role of VDAC-2 has been controversial. In humans, VDAC-2 is best known for its anti-apoptotic properties. In this Viewpoint, we associate the various functional studies on VDAC-2 with structural reports, to decode its unique behavior. The well-structured N-terminus, compact barrel form, differences in the loop regions, specific transmembrane segments and the abundance of thiols in VDAC-2 enable this isoform to perform a different subset of regulatory functions, establish anti-apoptotic features and contribute to gametogenesis. VDAC-2 structural features that demarcate it from VDAC-1 suggest that this particular isoform is better suited for regulating reactive oxygen species, steroidogenesis and mitochondria-associated endoplasmic reticulum membrane regulatory pathways, with ion transport forming a secondary role. A better understanding of the unique structural features of the VDAC family will aid in the design of inhibitors that could alleviate irregularities in VDAC-controlled pathways.

Keywords: apoptosis; cysteines; mitochondrial outer membrane; voltage-dependent anion channel; β-barrel proteins.

Fig. 1

Comparison of various cellular functions carried out by VDAC-1 and -2. VDAC-1 and -2 are 19-stranded β-barrel mitochondrial outer membrane proteins with a dynamic N-terminal helix that primarily stays docked in the pore. Both the barrel N (solid arrow, towards the viewer) and C termini (dashed arrow, away from the viewer) face the IMS side of mitochondria, although the flexibility of the N terminus may cause it to translocate to the cytosolic side. Notwithstanding the high sequence similarity between the two isoforms, subtle structural and sequencerelated differences such as cysteine content, barrel compactness, N-terminal extension and loop-specific differences endow them with the ability to execute different functions. VDAC-1 (left) forms the major route for metabolite transport and requires hexokinase binding to suppress its pro-apoptotic nature. In contrast, VDAC-2 (right) displays anti-apoptotic properties/features by actively binding and inhibiting Bcl-2 family members such as BCL2L1 and Bak. Cysteine residues are enriched in loop regions of VDAC-2 that are specifically oriented towards the IMS and confer protection from ROS build-up. Additionally, VDAC-2 also improves the cholesterol fostering ability of StAR protein. By and large, the VDAC family of channels is involved in apoptosis either by regulating the PTP complex or through oligomerization (lower panel). They are also involved in maintaining Ca²⁺ homeostasis within the cell, and are negatively regulated by interaction with tubulin. N-ter, N terminus; C-ter, C terminus; IMS, intermembrane space; MAM, mitochondria associated endoplasmic reticulum membrane; IMM, inner mitochondrial membrane. The overall barrel geometry of VDAC-1 and -2 is retained in the respective panels.