Elsevier

Mitochondrion

Volume 12, Issue 1, January 2012, Pages 24-34
Mitochondrion

Review
VDAC, a multi-functional mitochondrial protein as a pharmacological target

https://doi.org/10.1016/j.mito.2011.04.001Get rights and content

Abstract

Regulation of mitochondrial physiology requires an efficient exchange of molecules between mitochondria and the cytoplasm via the outer mitochondrial membrane (OMM). The voltage-dependent anion channel (VDAC) lies in the OMM and forms a common pathway for the exchange of metabolites between the mitochondria and the cytosol, thus playing a crucial role in the regulation of metabolic and energetic functions of mitochondria. VDAC is also recognized to function in mitochondria-mediated apoptosis and in apoptosis regulation via interaction with anti-apoptotic proteins, namely members of Bcl-2 family, and the pro-survival protein, hexokinase, overexpressed in many cancer types. Thus, VDAC appears to be a convergence point for a variety of cell survival and cell death signals, mediated by its association with various ligands and proteins. In this article, we review mammalian VDAC, specifically focusing on VDAC1, addressing its functions in cell life and the regulation of apoptosis and its involvement in several diseases. Additionally, we provide insight into the potential of VDAC1 as a rational target for novel therapeutics.

Section snippets

Overview

Research over the past decade has extended the prevailing view of the mitochondrion to include functions well beyond its critical bioenergetics role in supplying ATP. It is now recognized that mitochondria play a crucial role in cell signaling events, inter-organellar communication, aging, cell proliferation, diseases and in the regulation of apoptosis (programmed cell death). Thus, mitochondria are the venue for cellular decisions leading to cell life or death. Lying in the outer mitochondrial

The VDAC proteins and their channel activity

In higher eukaryotes, three VDAC isoforms have been characterized: VDAC1, VDAC2 and VDAC3, encoded by three separate genes (Shoshan-Barmatz et al., 2010). Although VDACs are highly conserved across species, the specific function of each isoform remains poorly understood. VDAC1 is the most abundant isoform in most cells, being ten times more prevalent than VDAC2 and 100 times more prevalent than VDAC3 in HeLa cells (De Pinto et al., 2010a). In recent work using STED microscopy, it was

VDAC structure

In 2008, the three-dimensional structure of VDAC1 was determined at atomic resolution by applying NMR to detergent-solubilized hVDAC (Hiller et al., 2008), by combining NMR and X-ray crystallography (Bayrhuber et al., 2008) and by lipidic bicelle crystallization, which produced a high-resolution X-ray structure of mouse VDAC within a bicellar environment (Ujwal et al., 2008). The three structures are almost identical, featuring a 19-stranded β-barrel and a 25 residue-long N-terminal α-helical

Effects of VDAC silencing and overexpression on cell life and death

Since VDAC1 regulates metabolic and energetic functions of mitochondria, its down-expression should affect cell metabolism and normal mitochondrial function. Indeed, silencing hVDAC1 expression in T-Rex-293 cells using shRNA resulted in reduced ATP production and a decrease in cell growth (Abu-Hamad et al., 2006). Furthermore, when HeLa cervical cancer cells stably expressing shRNA directed against hVDAC1 (Koren et al., 2010) were injected into nude mice, the development of a solid tumor was

Mitochondria-mediated apoptosis

In apoptosis, a cascade of cysteine protease enzymes, caspases, capable of cleaving targeted proteins, is activated, subsequently leading to organized cell demise. Defects in the regulation of apoptosis are often associated with disease and drug resistance (Johnstone et al., 2002), as well as with the ability of cells to evade apoptosis, a hallmark of cancer (Hanahan and Weinberg, 2000).

Two separate pathways leading to caspase activation have been characterized and are referred to as the

VDAC-associated proteins

Localization of VDAC1 to the OMM makes it a functional anchor point for molecules that interact with the mitochondria. VDAC1 displays binding sites for glycerol kinase, hexokinase and creatine kinase (Shoshan-Barmatz et al., 2010). Mitochondrial creatine kinase (MtCK), in its octameric state, interacts with VDAC1 (Schlattner et al., 2001) and causes decreased affinity of VDAC1 for HK and Bax (Vyssokikh et al., 2004). VDAC also forms complexes with other proteins, such as the ANT (Vyssokikh and

VDAC regulation

Various reagents were shown to interact with VDAC and modify its channel activity by increasing the probability of VDAC closure, thereby decreasing channel conductance (for review see Shoshan-Barmatz et al., 2008a, Shoshan-Barmatz et al., 2010, Shoshan-Barmatz and Gincel, 2003, Shoshan-Barmatz et al., 2006). Modification of VDAC activity by ROS and phosphorylation were also reported.

Mitochondria, VDAC and human diseases

Mitochondria-mediated apoptosis plays a crucial role in the pathophysiology of several diseases, including heart attack, stroke, cancer, mitochondrial enchephalomyopathies and aging, as well as neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) (Taylor and Turnbull, 2005). Since VDAC is a target of pro- and anti-apoptotic proteins and a key factor in mitochondria-mediated apoptosis, it may be involved in these diseases and

VDAC and reagent toxicity

VDAC is a prime target for therapeutic agents designed to modulate apoptosis (Shoshan-Barmatz et al., 2010). Indeed, several studies identified pharmacological agents that target VDAC to induce cancer cell death. These agents can be categorized into the following groups:

Concluding remarks

We have witnessed a significant accumulation of knowledge regarding the function of VDAC in recent years. Biochemical, molecular and biophysical approaches have advanced our knowledge of VDAC structure–function relationships, as well as of the remarkable diversity of regulatory mechanisms controlling VDAC function. Although a high-resolution structure has been determined for recombinant VDAC1, many questions concerning the architecture of the channel pore, the location of modulator-binding

Abbreviations

    ANT

    adenine nucleotide translocase

    Cyto c

    cytochrome c

    DIDS

    4,4′-diisothiocyanostilbene-2,2′-disulfonic acid

    HK

    hexokinase

    OMM

    outer mitochondrial membrane

    MMP

    mitochondrial membrane permeabilization

    MPT

    mitochondrial permeability transition

    NMR

    nuclear magnetic resonance

    PLB

    planar lipid bilayer

    PTP

    permeability transition pore

    ROS

    reactive oxygen species

    RuR

    ruthenium red

    VDAC

    voltage-dependent anion channel

Acknowledgments

This research was supported by grants from the Israel Science Foundation, the Israel Cancer Association and the Chief Scientist's Office, Ministry of Health, Government of Israel.

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