ReviewVDAC, a multi-functional mitochondrial protein as a pharmacological target
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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