ReviewVDAC, a multi-functional mitochondrial protein regulating cell life and death
Section snippets
Historical overview
In 2008, the structure of VDAC was determined almost simultaneously by three different groups, using different techniques (Bayrhuber et al., 2008, Hiller et al., 2008, Ujwal et al., 2008). The importance of this achievement can be best appreciated if one considers that only one other structure of an integral mitochondrial membrane protein responsible for metabolite transport, i.e. the adenine nucleotide translocase (ANT) carrier (Pebay-Peyroula et al., 2003), has been solved to date. The
VDAC purification: a common pattern
Soon after the discovery of a channel-forming component in mitochondria of Paramecium aurelia (Schein et al., 1976) and the finding that the outer mitochondrial membrane of a variety of cells contained the newly-defined voltage-dependent anion-selective channel (Colombini, 1979), researchers labored towards isolating the protein, with the aim of characterizing its functional and structural features.
The purification protocols developed to isolate VDAC from various tissues encountered an apparent
Methods employed for the study of VDAC channel activity
As for any membrane protein responsible for an exchange of solutes across a membrane, the functional properties of VDAC have been examined in reconstituted systems based on artificially prepared phospholipid bilayers. Two main membrane systems have been used to study the pore-forming activity of VDACs, i.e. vesicles or planar lipid bilayers (PLB). The former, historically used to detect the passage of labeled molecules, is less often employed, given the advantage of the smaller amount of active
The three-dimensional structure of hVDAC1
In 2008, the three-dimensional structure of isoform 1 of VDAC was determined at atomic resolution by three independent technical approaches (Bayrhuber et al., 2008, Hiller et al., 2008, Ujwal et al., 2008). The structure of human VDAC1 (hVDAC1) was solved in parallel by nuclear magnetic resonance spectroscopy (NMR) (Hiller et al., 2008) and by a novel approach combining nuclear magnetic resonance spectroscopy and X-ray crystallography (Bayrhuber et al., 2008). The three-dimensional structure of
VDAC genes
As detailed in Section 2.4, the evolution of VDAC sequences indicates that an ancestor gene lays at the origin of the various VDAC genes seen in most groups of organisms. Paralogs have appeared several times in the different lineages as a result of clearly different events. In Drosophilae, for example, segmental duplication has led to the highly divergent forms described in (Oliva et al., 2002). In S. cerevisiae, the two genes possibly are remnants of a genome duplication process (Kellis et
VDAC1 in the plasma membrane
The extra-mitochondrial localization of porin was shown for the first time by Thinnes and co-workers (Kayser et al., 1989, Thinnes et al., 1989; for reviews, see Bathori et al., 2000; De Pinto et al., 2010b), who fortuitously co-purified porin together with human transplantation antigens. Intrigued by this protein, they sequenced it by Edman degradation (Kayser et al., 1989) and called it porin 31HL. Later, they produced monoclonal antibodies against the N-terminal end of the protein (Babel et
VDAC silencing, overexpression and cell life and death
In recent years, RNA interference (RNAi) has been proven to be a powerful and specific approach for targeted RNA-dependent gene silencing and is rapidly become a central tool in the study of cell function in a wide range of biomedical applications (Gunsalus and Piano, 2005, Morita and Yoshida, 2002, Pushparaj et al., 2008). The mechanism of action of RNAi relies on the endogenous machinery responsible for post-transcriptional gene silencing regulation by micro-RNAs (miRNA) (Chekulaeva and
Mitochondria-mediated apoptosis
Cells can undergo death by several modes. One such route involves programmed cell death, or apoptosis. Apoptotic cell death occurs during many physiological conditions, such as during embryonic or immune system development, or in response to infection, DNA damage or disease (Danial and Korsmeyer, 2004, Elmore, 2007, Green, 2003, Hickman, 2002, Johnstone et al., 2002, Olson and Kornbluth, 2001, Tatton and Olanow, 1999). In apoptosis, a cascade of caspases, cysteine protease enzymes capable of
VDAC-associated proteins
VDAC1 localization in the OMM makes it not only a major gate for molecules that need to access and/or exit the IMS but also makes VDAC a functional anchor point for molecules that interact with the mitochondria. VDAC1, moreover, plays an important role in the coordination of communication between the mitochondria and the rest of the cell. A substantial aspect of this management involves the transient formation of complexes with other proteins (Vyssokikh et al., 2004). It has been suggested that
VDAC regulation by non-protein modulators
In addition to Ca2+ being proposed to modulate VDAC activity, various other reagents were shown to interact with VDAC and modify its channel activity by increasing the probability of VDAC closure. Moreover, it was demonstrated that VDAC closure by various reagents resulted in the inhibition of PTP opening, Cyto c release and apoptotic cell death. As most of these reagents have been previously discussed (for review, see Shoshan-Barmatz et al., 2006, Shoshan-Barmatz et al., 2008a, Shoshan-Barmatz
Mitochondria, ROS and oxidative stress
In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must, therefore, exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of ROS exceeds the capacity of mitochondrial and cellular anti-oxidant defenses to remove these toxic species. Unbalanced oxidation/reduction of macromolecular cell components is involved in the pathogenesis of
VDAC phosphorylation, its function in apoptosis and modulation by associated proteins
Protein phosphorylation is a major post-translation modification regulatory system, modulating protein stability, enzymatic activity, sub-cellular localization, the ability to interact with binding partners, and more (Cohen, 2002). A cohort of protein kinases have been detected in mitochondria, e.g. protein kinase A (PKA) (Schwoch et al., 1990), different isoforms of protein kinase C (PKC) (Majumder et al., 2000), and components of the MAPK signaling pathway (Yuryev et al., 2000), glycogen
VDAC and human diseases
There is a substantial amount of evidence relating mitochondrial apoptosis to human disease (Mattson, 2000, Olson and Kornbluth, 2001). Mitochondria-mediated apoptosis plays a crucial role in the pathophysiology of several diseases, such as heart attack, stroke, cancer, mitochondrial enchephalomyopathies, and aging, as well as in neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) (Alexander et
VDAC and reagent toxicity
As presented above, mitochondria play a central role in the execution of apoptosis, with VDAC being a critical component in this pathway. As such, VDAC can be considered as a prime target for therapeutic agents designed to modulate apoptosis (Granville and Gottlieb, 2003). Indeed, several studies have demonstrated VDACs as the pharmacologic target of novel molecules inducing cancer cell death (Table 2). The cancer-selectivity of VDAC-dependent cytotoxic agents could be related to the higher
Concluding remarks
We have witnessed a significant accumulation of knowledge regarding the function of VDAC in recent years. Following the identification of VDAC as the OMM channel, much has been learned about the protein’s structure–function relationships, the biochemical and molecular basis of its activation and inactivation, and the manner by which VDAC activity is modulated within the cell. Biochemical and molecular approaches have revealed a remarkable diversity of regulatory mechanisms controlling VDAC
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 to VSB, and from the Max Planck Society to M.Z. who is also supported by a Heisenberg fellowship (ZW 71/2-1, 3-1). The support from Phil and Sima Needleman to VSB and of University of Catania (PRA 2006–2008), FIRB RBRN07BMCT, PRIN MIUR 2008SW44CS_004 to VDP are highly acknowledged.
We thank Abu-Hamad and Keshet
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