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BBA - Biomembranes (v.1818, #6)

Editorial Board (pp. i).

VDAC structure, function, and regulation of Mitochondrial and Cellular Metabolism by Tatiana K. Rostovtseva (pp. 1437-1437).

VDAC, The early days by Marco Colombini; Carmen A. Mannella (pp. 1438-1443).

VDAC is now universally accepted as the channel in the mitochondrial outer membrane responsible for metabolite flux in and out of mitochondria. Its discovery occurred over two independent lines of investigation in the 1970s and 80s. This retrospective article describes the history of VDAC's discovery and how these lines merged in a collaboration by the authors. The article was written to give the reader a sense of the role played by laboratory environment, personalities, and serendipity in the discovery of the molecular basis for the unusual permeability properties of the mitochondrial outer membrane. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► the discovery of the VDAC channel by recording its electrophysiological properties ► the discovery of the VDAC channel by electron microscopy ► the interesting historical events surrounding the discoveries

Keywords: Mitochondria; Channel; Planar membrane; Electron microscopy; Crystalline arrays; Outer membrane

The role of VDAC in cell death: Friend or foe? by Kyle S. McCommis; Christopher P. Baines (pp. 1444-1450).

As the voltage-dependent anion channel (VDAC) forms the interface between mitochondria and the cytosol, its importance in metabolism is well understood. However, research on VDAC's role in cell death is a rapidly growing field, unfortunately with much confusing and contradictory results. The fact that VDAC plays a role in outer mitochondrial membrane permeabilization is undeniable, however, the mechanisms behind this remain very poorly understood. In this review, we will summarize the studies that show evidence of VDAC playing a role in cell death. To begin, we will discuss the evidence for and against VDAC's involvement in mitochondrial permeability transition (MPT) and attempt to clarify that VDAC is not an essential component of the MPT pore (MPTP). Next, we will evaluate the remaining literature on VDAC in cell death which can be divided into three models: proapoptotic agents escaping through VDAC, VDAC homo- or hetero-oligomerization, or VDAC closure resulting in outer mitochondrial membrane permeabilization through an unknown pathway. We will then discuss the growing list of modulators of VDAC activity that have been associated with induction/protection against cell death. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Review the evidence both for and against a role for VDACs in mitochondrial permeability transition. ► Review the literature regarding the role of VDACs in mitochondrial-dependent apoptosis. ► Discuss the factors that regulate VDAC permeability and how they influence cell death.

Keywords: VDAC; Mitochondrion; Permeability transition; Apoptosis; Necrosis

Does the voltage dependent anion channel modulate cardiac ischemia–reperfusion injury? by Samarjit Das; Charles Steenbergen; Elizabeth Murphy (pp. 1451-1456).

The voltage dependent anion channel (VDAC) provides exchange of metabolites, anions, and cations across the outer mitochondrial membrane. VDAC provides substrates and adenine nucleotides necessary for electron transport and therefore plays a key role in regulating mitochondrial bioenergetics. VDAC has also been suggested to regulate the response to cell death signaling. Emerging data show that VDAC is regulated by protein–protein interactions as well as by post-translational modifications. This review will focus on the regulation of VDAC and its potential role in regulating cell death in cardiac ischemia–reperfusion. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Discusses regulation of VDAC by protein–protein interactions and post-translational modifications. ► Discusses the role of the open versus the close state in VDAC and cell death. ► Discusses the role of VDAC in ischemia–reperfusion injury.

Keywords: Mitochondrion; Ischemia; Cardioprotection; Phosphorylation

VDAC structure, selectivity, and dynamics by Marco Colombini (pp. 1457-1465).

VDAC channels exist in the mitochondrial outer membrane of all eukaryotic organisms. Of the different isoforms present in one organism, it seems that one of these is the canonical VDAC whose properties and 3D structure are highly conserved. The fundamental role of these channels is to control the flux of metabolites between the cytosol and mitochondrial spaces. Based on many functional studies, the fundamental structure of the pore wall consists of one α helix and 13 β strands tilted at a 46° angle. This results in a pore with an estimated internal diameter of 2.5nm. This structure has not yet been resolved. The published 3D structure consists of 19 β strands and is different from the functional structure that forms voltage-gated channels. The selectivity of the channel is exquisite, being able to select for ATP over molecules of the same size and charge. Voltage gating involves two separate gating processes. The mechanism involves the translocation of a positively charged portion of the wall of the channel to the membrane surface resulting in a reduction in pore diameter and volume and an inversion in ion selectivity. This mechanism is consistent with experiments probing changes in selectivity, voltage gating, kinetics and energetics. Other published mechanisms are in conflict with experimental results. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► The structure of the VDAC channel. ► The molecular basis for selectivity of VDAC. ► The molecular basis for voltage gating of VDAC.

Keywords: Mitochondrion; Outer membrane; Channel; Voltage-gating; Selectivity; Permeability

VDAC isoforms in mammals by Angela Messina; Simona Reina; Francesca Guarino; Vito De Pinto (pp. 1466-1476).

VDACs (Voltage Dependent Anion selective Channels) are a family of pore-forming proteins discovered in the mitochondrial outer membrane. In the animal kingdom, mammals show a conserved genetic organization of the VDAC genes, corresponding to a group of three active genes. Three VDAC protein isoforms thus exist. From a historically point of view most of the data collected about this protein refer to the VDAC1 isoform, the first to be identified and also the most abundant in the organisms. In this work we compare the information available about the three VDAC isoforms, with a special emphasis upon the human proteins, here considered prototypical of the group, and we try to shed some light on specific functional roles of this apparently redundant group of proteins. A new hypothesis about the VDAC(s) involvement in ROS control is proposed. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► VDAC isoforms in eutheria are a well conserved family of outer membrane mitochondrial protein. ► The 3 VDAC isoforms in mitochondria have distinct roles in the cell. ► VDAC1 is the most abundant pore, pro-apoptotic and specific for low amplitude Ca²⁺ signals. ► VDAC2 has a longer N-end, similar activity than VDAC1 and is considered anti-apoptotic. ► VDAC3 is the least known, has a poor pore-forming activity and additional functions in cell.

Keywords: VDAC isoform; Mitochondria; Ca; ²⁺; ROS; N-terminal sequence

Voltage-dependant anion channels: Novel insights into isoform function through genetic models by Adithya Raghavan; Tatiana Sheiko; Brett H. Graham; William J. Craigen (pp. 1477-1485).

Voltage-dependant Anion Channels, also known as mitochondrial porins, are pore-forming proteins located in the mitochondrial outer membrane (MOM) that, in addition to forming complexes with other proteins that localize to the MOM, also function as the main conduit for transporting metabolites between the cytoplasm and mitochondria. VDACs are encoded by a multi-member gene family, and the number of isoforms and specific functions of VDACs varies between species. Translating the well-described in vitro characteristics of the VDAC isoforms into in vivo functions has been a challenge, with the generation of animal models of VDAC deficiency providing much of the available information about isoform-specific roles in biology. Here, we review the approaches used to create these insect and mammalian animal models, and the conclusions reached by studying the consequences of loss of function mutations on the genetic, physiologic, and biochemical properties of the resulting models. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Animal models lacking VDAC isoforms have been created. ► Drosophila and mouse models share similar features. ► VDACs have roles in fertility, learning and memory, glucose homeostasis, and apoptosis. ► The models have been instrumental in identifying the function of each VDAC protein.

Keywords: Animal model; Voltage-dependent anion channel; Mouse knock out; Drosophila; Porin; Mitochondria

Plant VDAC: Facts and speculations by Homble Fabrice Homblé; Eva-Maria Krammer; Prevost Martine Prévost (pp. 1486-1501).

The voltage-dependent anion-selective channel (VDAC) is the most abundant protein in the mitochondrial outer membrane and the major transport pathway for a large variety of compounds ranging from ions to large polymeric molecules such as DNA and tRNA. Plant VDACs feature a secondary structure content and electrophysiological properties akin to those of VDACs from other organisms. They however undergo a specific regulation. The general importance of VDAC in plant physiology has only recently emerged. Besides their role in metabolite transport, plant VDACs are also involved in the programmed cell death triggered in response to biotic and abiotic stresses. Moreover, their colocalization in non-mitochondrial membranes suggests a diversity of function. This review summarizes our current understanding of the structure and function of plant VDACs. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.Display Omitted► We review our current understanding and knowledge of plant VDACs. ► Their structure, function and subcellular localization are addressed. ► Characteristic sequence motifs of plant VDACs are revisited. ► A 3D model is proposed as a working hypothesis for future studies on plant VDACs.

Keywords: Abbreviations; ATR-FTIR; attenuated total reflection Fourier transform infrared spectroscopy; AtVDAC; Arabidopsis thaliana; VDAC; CD; circular dichroism spectroscopy; GmVDAC; Glycine max; VDAC; hVDAC1; human VDAC1; LjVDAC; Lotus japonicus; VDAC; MIM; mitochondrial inner membrane; MOM; mitochondrial outer membrane; MSA; multiple sequence alignment; mVDAC1; mouse VDAC1; PcVDAC32; Phaseolus coccineus; VDAC32; PCD; programmed cell deathVDAC; Mitochondrion; Beta-barrel; Programmed cell death; Sterol; Protein structure

Phylogenetic and coevolutionary analysis of the β-barrel protein family comprised of mitochondrial porin (VDAC) and Tom40 by Denice C. Bay; Mohamed Hafez; Matthew J. Young; Deborah A. Court (pp. 1502-1519).

Beta-barrel proteins are the main transit points across the mitochondrial outer membrane. Mitochondrial porin, the voltage-dependent, anion-selective channel (VDAC), is responsible for the passage of small molecules between the mitochondrion and the cytosol. Through interactions with other mitochondrial and cellular proteins, it is involved in regulating organellar and cellular metabolism and likely contributes to mitochondrial structure. Tom40 is part of the translocase of the outer membrane, and acts as the channel for passage of preproteins during their import into the organelle. These proteins appear to share a common evolutionary origin and structure. In the current study, the evolutionary relationships between and within both proteins were investigated through phylogenetic analysis. The two groups have a common origin and have followed independent, complex evolutionary pathways, leading to the generation of paralogues in animals and plants. Structures of diverse representatives were modeled, revealing common themes rather than sites of high identity in both groups. Within each group, intramolecular coevolution was assessed, revealing a new set of sites potentially involved in structure–function relationships in these molecules. A weak link between Tom40 and proteins related to the mitochondrial distribution and morphology protein, Mdm10, was identified. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Mitochondrial porins and Tom40 are related but have unique evolutionary histories. ► Both porin and Tom40 families contain highly divergent sequences. ► Coevolutionary analysis reveals potentially important sites in Tom40 and porin. ► Divergent porin and Tom40 sequences modeled on the crystal structure of mouse VDAC1. ► Mdm10-like proteins may have origins as Tom40 proteins.

Keywords: Abbreviations; βx; beta strand x (example β1); HsVDACx; isoform x of VDAC from; Homo sapiens; Lx–y; loop between beta strands x and y; LDAO; lauryldimethylamine oxide; MI; mutual information; MIB; mutual information considering amino acid bias; MIBP; mutual information considering amino acid bias and physicochemical properties; MIP; mutual information considering physicochemical properties; ML; maximum likelihood; NJ; Neighbor Joining; MmVDACx; isoform x of VDAC from; Mus musculus; SAM; sorting and assembly machinery; TOM; translocase of the mitochondrial outer membrane; VDAC; voltage-dependent anion-selective channelMitochondrial porin; VDAC; Tom40; Phylogeny; Coevolution; Mdm10

VDAC proteomics: Post-translation modifications by Janos Kerner; Kwangwon Lee; Bernard Tandler; Charles L. Hoppel (pp. 1520-1525).

Voltage-dependent anion channels are abundant mitochondrial outer membrane proteins expressed in three isoforms, VDAC1-3, and are considered as “mitochondrial gatekeepers”. Most tissues express all three isoforms. The functions of VDACs are several-fold, ranging from metabolite and energy exchange to apoptosis. Some of these functions depend on or are affected by interaction with other proteins in the cytosol and intermembrane space. Furthermore, the function of VDACs, as well as their interaction with other proteins, is affected by posttranslational modification, mainly phosphorylation. This review summarizes recent findings on posttranslational modification of VDACs and discusses the physiological outcome of these modifications. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Phosphorylation of VDAC on serine, threonine, and tyrosine has been detected. ► Phosphorylation of serine 12 and 103 decreases degradation of VDAC1 that is associated with increased apoptosis. ► Phosphorylation of serine 193 prevents cell death. ► Lysine acetylation has been detected but functional consequences have not been studied.

Keywords: Mitochondrial outer membrane; Acetyl-lysine; Phosphorylation

VDAC inhibition by tubulin and its physiological implications by Tatiana K. Rostovtseva; Sergey M. Bezrukov (pp. 1526-1535).

Regulation of mitochondrial outer membrane (MOM) permeability has dual importance: in normal metabolite and energy exchange between mitochondria and cytoplasm, and thus in control of respiration, and in apoptosis by release of apoptogenic factors into the cytosol. However, the mechanism of this regulation involving the voltage-dependent anion channel (VDAC), the major channel of MOM, remains controversial. For example, one of the long-standing puzzles was that in permeabilized cells, adenine nucleotide translocase is less accessible to cytosolic ADP than in isolated mitochondria. Still another puzzle was that, according to channel-reconstitution experiments, voltage regulation of VDAC is limited to potentials exceeding 30mV, which are believed to be much too high for MOM. We have solved these puzzles and uncovered multiple new functional links by identifying a missing player in the regulation of VDAC and, hence, MOM permeability — the cytoskeletal protein tubulin. We have shown that, depending on VDAC phosphorylation state and applied voltage, nanomolar to micromolar concentrations of dimeric tubulin induce functionally important reversible blockage of VDAC reconstituted into planar phospholipid membranes. The voltage sensitivity of the blockage equilibrium is truly remarkable. It is described by an effective “gating charge” of more than ten elementary charges, thus making the blockage reaction as responsive to the applied voltage as the most voltage-sensitive channels of electrophysiology are. Analysis of the tubulin-blocked state demonstrated that although this state is still able to conduct small ions, it is impermeable to ATP and other multi-charged anions because of the reduced aperture and inversed selectivity. The findings, obtained in a channel reconstitution assay, were supported by experiments with isolated mitochondria and human hepatoma cells. Taken together, these results suggest a previously unknown mechanism of regulation of mitochondrial energetics, governed by VDAC interaction with tubulin at the mitochondria–cytosol interface. Immediate physiological implications include new insights into serine/threonine kinase signaling pathways, Ca2⁺ homeostasis, and cytoskeleton/microtubule activity in health and disease, especially in the case of the highly dynamic microtubule network which is characteristic of cancerogenesis and cell proliferation. In the present review, we speculate how these findings may help to identify new mechanisms of mitochondria-associated action of chemotherapeutic microtubule-targeting drugs, and also to understand why and how cancer cells preferentially use inefficient glycolysis rather than oxidative phosphorylation (Warburg effect). This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Main in vitro and in vivo findings on VDAC blockage by tubulin are presented. ► VDAC phosphorylation state and applied voltage define blockage equilibrium. ► IC50 of the blockage spans the range of nanomolar to micromolar tubulin concentration. ► Immediate implications for cell signaling in health and disease are discussed.

Keywords: Abbreviations; CTT; C-terminal tail; GSK3β; glycogen synthase kinase-3β; MOM; mitochondrial outer membrane; MT; microtubule; OxPhos; oxidative phosphorylation; PKA; cyclic AMP-dependent protein kinase A; VDAC; voltage-dependent anion channelVoltage-dependent anion channel; Mitochondria; Microtubule; phosphorylation; Signaling network; Selectivity

Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect by John J. Lemasters; Ekhson L. Holmuhamedov; Christoph Czerny; Zhi Zhong; Eduardo N. Maldonado (pp. 1536-1544).

Voltage dependent anion channels (VDAC) are highly conserved proteins that are responsible for permeability of the mitochondrial outer membrane to hydrophilic metabolites like ATP, ADP and respiratory substrates. Although previously assumed to remain open, VDAC closure is emerging as an important mechanism for regulation of global mitochondrial metabolism in apoptotic cells and also in cells that are not dying. During hepatic ethanol oxidation to acetaldehyde, VDAC closure suppresses exchange of mitochondrial metabolites, resulting in inhibition of ureagenesis. In vivo, VDAC closure after ethanol occurs coordinately with mitochondrial uncoupling. Since acetaldehyde passes through membranes independently of channels and transporters, VDAC closure and uncoupling together foster selective and more rapid oxidative metabolism of toxic acetaldehyde to nontoxic acetate by mitochondrial aldehyde dehydrogenase. In single reconstituted VDAC, tubulin decreases VDAC conductance, and in HepG2 hepatoma cells, free tubulin negatively modulates mitochondrial membrane potential, an effect enhanced by protein kinase A. Tubulin-dependent closure of VDAC in cancer cells contributes to suppression of mitochondrial metabolism and may underlie the Warburg phenomenon of aerobic glycolysis. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► Voltage dependent anion channels (VDAC) required for mitochondrial outer membrane permeability. ► VDAC emerging as important regulator of mitochondrial metabolism. ► Selective oxidation of toxic acetaldehyde after ethanol fostered by VDAC closure and uncoupling. ► Tubulin-dependent VDAC closure enhanced by protein kinase A and antagonized by GSK3β. ► Contribution of VDAC closure to suppression of mitochondrial metabolism in Warburg effect.

Keywords: Acetaldehyde; Glycogen synthase kinase-3β; Hepatoma; Liver; mitochondrion; Protein kinase A; Tubulin

Regulation of respiration in muscle cells in vivo by VDAC through interaction with the cytoskeleton and MtCK within Mitochondrial Interactosome by Rita Guzun; Marcela Gonzalez-Granillo; Minna Karu-Varikmaa; Alexei Grichine; Yves Usson; Tuuli Kaambre; Karen Guerrero-Roesch; Andrey Kuznetsov; Uwe Schlattner; Valdur Saks (pp. 1545-1554).

This review describes the recent experimental data on the importance of the VDAC–cytoskeleton interactions in determining the mechanisms of energy and metabolite transfer between mitochondria and cytoplasm in cardiac cells. In the intermembrane space mitochondrial creatine kinase connects VDAC with adenine nucleotide translocase and ATP synthase complex, on the cytoplasmic side VDAC is linked to cytoskeletal proteins. Applying immunofluorescent imaging and Western blot analysis we have shown that β2-tubulin coexpressed with mitochondria is highly important for cardiac muscle cells mitochondrial metabolism. Since it has been shown by Rostovtseva et al. that αβ-heterodimer of tubulin binds to VDAC and decreases its permeability, we suppose that the β-tubulin subunit is bound on the cytoplasmic side and α-tubulin C-terminal tail is inserted into VDAC. Other cytoskeletal proteins, such as plectin and desmin may be involved in this process. The result of VDAC-cytoskeletal interactions is selective restriction of the channel permeability for adenine nucleotides but not for creatine or phosphocreatine that favors energy transfer via the phosphocreatine pathway. In some types of cancer cells these interactions are altered favoring the hexokinase binding and thus explaining the Warburg effect of increased glycolytic lactate production in these cells. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► We review the recent data on the interaction of VDAC with cytoskeletal proteins and mitochondrial creatine kinase (MtCK). ► We describe mitochondrial interactosome as a structural unit involved in regulation of oxidative phosphorylation. ► We discuss the influence of VDAC–tubulin interaction on mitochondrial functioning in healthy cardiomyocytes. ► The role of the interaction of VDAC with tubulin and MtCK in determining the pathways of the energy transfer is discussed.

Keywords: Mitochondria; Voltage-dependent anion channel; Cytoskeleton; Tubulin; Phosphotransfer network; Creatine kinase system

VDAC blockage by phosphorothioate oligonucleotides and its implication in apoptosis by Wenzhi Tan (pp. 1555-1561).

Apoptosis is a crucial process that regulates the homeostasis of multicellular organisms. Impaired apoptosis contributes to cancer development, while enhanced apoptosis is detrimental in neurodegenerative diseases. The intrinsic apoptotic pathway is initiated by cytochrome c release from mitochondria. Research published in the recent decade has suggested that cytochrome c release can be influenced by the conducting states of VDAC, the channel in the mitochondrial outer membrane (MOM) responsible for metabolite flux. This review will describe the evidence that VDAC gating or blockage and subsequent changes in MOM permeability influence cytochrome c release and the onset of apoptosis. The blockage of VDAC by G3139, a proapoptotic phosphorothioate oligonucleotide, provides strong evidence for the role of VDAC in the initiation of apoptosis. The proapoptotic activity and VDAC blockage are linked in that both require the PS (phosphorothioate) modification, both are enhanced by an increase in oligonucleotide length, and both are insensitive to the nucleotide sequence. Thus, the mitochondrial outer membrane permeability regulated by VDAC gating may play an important role in mitochondrial function and in the control of apoptosis. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► G3139 closes VDAC channel through its phosphorothioate modification. ► G3139 induces cell death partially through its interaction with VDAC. ► Phosphorothioate oligonucleotides target VDAC specifically at sub-micromolar concentrations. ► VDAC closure may lead to cytochrome c release from mitochondria, followed by apoptotic cascades.

Keywords: Abbreviations; ANT; adenine nucleotide translocator; ER; endoplasmic reticulum; MIM; mitochondrial inner membrane; MOM; mitochondrial outer membrane; PO; phosphodiester; PS; phosphorothioate; PTP; permeability transition pore; ROS; reactive oxygen speciesG3139; VDAC; Apoptosis; Phosphorothioate; Oligonucleotide; Mitochondria

Solution NMR spectroscopic characterization of human VDAC-2 in detergent micelles and lipid bilayer nanodiscs by Tsyr-Yan Yu; Thomas Raschle; Sebastian Hiller; Gerhard Wagner (pp. 1562-1569).

Three isoforms of the human voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, are crucial regulators of mitochondrial function. Numerous studies have been carried out to elucidate biochemical properties, as well as the three-dimensional structure of VDAC-1. However, functional and structural studies of VDAC-2 and VDAC-3 at atomic resolution are still scarce. VDAC-2 is highly similar to VDAC-1 in amino acid sequence, but has substantially different biochemical functions and expression profiles. Here, we report the reconstitution of functional VDAC-2 in lauryldimethylamine-oxide (LDAO) detergent micelles and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer nanodiscs. We find that VDAC-2 is properly folded in both membrane-mimicking systems and that structural and functional characterization by solution NMR spectroscopy is feasible. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► The VDAC-2 isoform can be refolded in detergent micelles suitable for NMR spectroscopy. ► VDAC-2 can be reconstituted into phospholipid nanodiscs and is more stable than in micelles. ► VDAC-2 in nanodiscs is suitable for NMR structure determination with triple-resonance and NOE data.

Keywords: VDAC; Mitochondrion; NMR spectroscopy; Micelle; Nanodisc; Membrane protein

Plasmalemmal VDAC controversies and maxi-anion channel puzzle by Ravshan Z. Sabirov; Petr G. Merzlyak (pp. 1570-1580).

The maxi-anion channel has been observed in many cell types from the very beginning of the patch-clamp era. The channel is highly conductive for chloride and thus can modulate the resting membrane potential and play a role in fluid secretion/absorption and cell volume regulation. A wide nanoscopic pore of the maxi-anion channel permits passage of excitatory amino acids and nucleotides. The channel-mediated release of these signaling molecules is associated with kidney tubuloglomerular feedback, cardiac ischemia/hypoxia, as well as brain ischemia/hypoxia and excitotoxic neurodegeneration. Despite the ubiquitous expression and physiological/pathophysiological significance, the molecular identity of the maxi-anion channel is still obscure. VDAC is primarily a mitochondrial protein; however several groups detected it on the cellular surface. VDAC in lipid bilayers reproduced the most important biophysical properties of the maxi-anion channel, such as a wide nano-sized pore, closure in response to moderately high voltages, ATP-block and ATP-permeability. However, these similarities turned out to be superficial, and the hypothesis of plasmalemmal VDAC as the maxi-anion channel did not withstand the test by genetic manipulations of VDAC protein expression. VDAC on the cellular surface could also function as a ferricyanide reductase or a receptor for plasminogen kringle 5 and for neuroactive steroids. These ideas, as well as the very presence of VDAC on plasmalemma, remain to be scrutinized by genetic manipulations of the VDAC protein expression. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.► The maxi-anion channel and VDAC share common biophysical properties. ► The maxi-anion channel activity does not correlate with VDAC expression. ► VDAC on the cellular surface could function as a ferricyanide reductase, as a receptor for plasminogen kringle 5 or neuroactive steroids. ► The ideas of non-channel functions of VDAC remain to be scrutinized by genetic manipulations.

Keywords: Abbreviations; VDAC; voltage-dependent anion channel; pl-VDAC; plasmalemmal VDAC; mt-VDAC; mitochondrial VDAC; PEG; polyethylene glycol; PMET; plasma membrane electron transportMaxi-anion channel; VDAC; Volume-sensitive chloride channel; Purinergic signaling; ATP release; Glutamate release

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BBA - Biomembranes (v.1818, #6)