1.B.8 The Mitochondrial and Plastid Porin (MPP) Family

Porins of the MPP family are found in eukaryotic organelles. The organelles include mitochondria of many eukaryotes as well as chloroplasts and plastids of plants. The best characterized members of the MPP family are the voltage-dependent anion-selective channel (VDAC) porins in the mitochondrial outer membrane. These porins have an estimated channel diameter of 2.5-3 nm. Topological models have been proposed in which VDAC consists of an N-terminal, globular α-helix and (1) 12 or 13 β-strands, (2) 16 β-strands or (3) 19 β-strands (now favored; see below) (Casadio et al., 2002). VDAC also appears to be present in plasma membranes (De Pinto et al., 2010). Prostacyclin receptor-mediated ATP release from ethrocytes requires VDAC (Sridharan et al., 2011).  Phylogenetic analyses of eukaryotic VDAC proteins from diverse organisms have been reported (Wojtkowska et al. 2012). Over-oxidation of cysteines and succinylation of cysteines in VDACs has been noticed (Saletti et al. 2018).

A murine VDAC, VDAC-1, exhibits more than one topological type due to the use of alternative first exons. Thus, two different porins, differing only with respect to their N-termini, have been identified. One porin isoform (plasmalemmal VDAC-1) has a hydrophobic leader peptide that targets the protein through the golgi apparatus to the plasma membrane; the other isoform (mitochondrial VDAC-1) is translocated to the outer mitochondrial membrane because it lacks the N-terminal hydrophobic leader. The former is believed to account for the plasma membrane Maxi (large conductance) Cl- channel (Bahamonde et al., 2003). 

VDACs play a role in forming the mitochondrial permeability transition pore (PTP) which is important for Ca2+ homeostasis and programmed cell death. PTP is triggered by Ca2+ influx into mitochondria, and VDAC is permeable to Ca2+. It is also regulated by various compounds such as glutamate, NADH and nucleotides. VDAC has two nucleotide binding sites (Yehezkel et al., 2006). In VDAC1 the two cysteine residues seem not to be required for apoptosis or VDAC1 oligomerization (Aram et al., 2010).  Ions interact intimately with the inner walls of the channel and are selected by their 3-dimensional structure, not merely by their size and charge (Colombini 2016).  The N-terminus acts not as a gate on a stable barrel, but rather stabilizes the barrel, preventing its shift into a partially collapsed, low-conductance, closed state (Shuvo et al. 2016).

Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. Misfolded mutant SOD1 binds directly to VDAC1. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of channels when reconstituted in a lipid bilayer (Israelson et al., 2010). 

VDAC-protein interactions for each mammalian isoform (VDAC1, 2 and 3)  showed that VDAC1 is mainly involved in the maintenance of cellular homeostasis and in pro-apoptotic processes, whereas VDAC2 displays an anti-apoptotic role, while VDAC3 may contribute to mitochondrial protein quality control and act as a marker of oxidative status (Caterino et al. 2017). In pathological conditions, namely neurodegenerative and cardiovascular diseases, both VDAC1 and VDAC2 establish abnormal interactions aimed to counteract the mitochondrial dysfunction which contributes to end-organ damage.

Persistent opening of permeability transition pore,PTP, creates a bioenergetic crisis with collapse of the membrane potential, ATP depletion, Ca2+ deregulation, and release of proteins such as cytochrome c into the cytoplasm. These events promote cell death. The PTP traverses the inner and outer membranes and involves the ATP/ADP exchanger (ANT) in the inner membrane and VDAC in the other membrane (Cesura et al., 2003). A calcium-triggered conformational change of the mitochondrial phosphate carrier (PiC), facilitated by cyclophilin-D (CyP-D), may induce pore opening. This is enhanced by an association of the PiC with the 'c' conformation of the ANT. Agents that modulate pore opening may act on either or both the PiC and the ANT (Leung and Halestrap, 2008). Chitosan quaternary ammonium salts induce mitochondrial PTP opening (Xia et al. 2020).

The selective anti-tumour agent erastin causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin. Using purified mitochondria expressing a single VDAC isoform, erastin alters the permeability of the outer mitochondrial membrane by binding directly to VDAC2. Thus, ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway (Yagoda et al., 2007).

VDACs form 19-stranded beta barrels with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion (Hiller et al., 2010). In the presence of cholesterol, recombinant VDAC-1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. The NMR measurements revealed the binding sites of VDAC-1 for the Bcl-2 protein, Bcl-x(L), for reduced beta-nicotinamide adenine dinucleotide, and for cholesterol. Bcl-x(L) interacts with the VDAC barrel laterally at strands 17 and 18 (Hiller et al., 2008). The position of the voltage-sensing N-terminal segment is oriented against the interior wall, causing a partial narrowing at the center of the pore. This segment is ideally positioned to regulate the conductance of ions and metabolites passing through the VDAC pore (Ujwal et al., 2008). 

Mitochondria import 90-99% of their proteins from the cytosol. Three protein families including Sam50, VDAC and Tom40 together with Mdm10 compose the set of integral beta-barrel proteins embedded in the mitochondrial outer membrane in S. cerevisiae (MOM) (Zeth 2010). The 16-stranded Sam50 protein forms part of the sorting and assembly machinery (SAM) and shows a clear evolutionary relationship to members of the bacterial Omp85 family (1.B.33). VDAC and Tom40 both adopt the same fold with 19 probable TMSs. Tom40 is in the TOM complex (3.A.8). Models of Tom40 and Sam50 have been developed using X-ray structures of related proteins. These models have been analyzed with respect to properties such as conservation and charge distribution yielding features related to their individual functions (Zeth 2010). 

The gene for VDAC1 in humans is over-expressed in many cancer types, and silencing of VDAC1 expression inhibits tumor development. Along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death (Shoshan-Barmatz et al. 2015).

The mitochondrial permeability transition pore complex (PTPC) is involved in the control of the mitochondrial membrane permeabilization during apoptosis, necrosis and autophagy. Indeed, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), two major components of the PTPC, are the targets of a variety of proapoptotic inducers. Verrier et al. 2004 identified some of the interacting partners of ANT. During chemotherapy-induced apoptosis, some of these interactions were constant (e.g. ANT-VDAC), whereas others changed. Glutathione-S-transferase (GST) also interacts. This interaction is lost during apoptosis induction, suggesting that GST behaves as an endogenous repressor of PTPC and ANT pore opening. Thus, ANT is connected to mitochondrial proteins as well as to proteins from other organelles such as the endoplasmic reticulum, forming a dynamic polyprotein complex. Changes within this ANT interactome coordinate the lethal response of cells to apoptosis induction (Verrier et al. 2004).

Under cellular stress, human VDACs hetero-oligomerize and coaggregate with proteins that can form amyloidogenic and neurodegenerative deposits, implicating a role for VDACs in proteotoxicity. Gupta and Mahalakshmi 2019 mapped aggregation-prone regions of human VDACs, using isoform 3 as the model VDAC, and showed that the region comprising strands beta7-beta9 is aggregation prone. An alpha1-beta7-beta9 interaction (involving the hVDAC3 N-terminal alpha1 helix) can lower protein aggregation, whereas perturbations of this interaction promote VDAC aggregation. hVDAC3 aggregation proceeds via a partially unfolded structure.

VDACs 1 - 3, also called porins 1 - 3 or Por1-3) regulate the formation of the mitochondrial protein import gate in the OM, the translocase of the outer membrane (TOM) complex, and its dynamic exchange between the major form of a trimer and the minor form of a dimer (Endo and Sakaue 2019). The TOM complex dimer lacks the core subunit, Tom22, and mediates the import of a subset of mitochondrial proteins while the TOM complex trimer facilitates the import of most other mitochondrial proteins. Porins interact with both a translocating inner membrane (IM) protein like a carrier protein accumulated at the small TIM chaperones in the intermembrane space and the TIM22 complex, a downstream translocator in the IM for carrier protein import. Porins (VDACs) thereby facilitate the efficient transfer of carrier proteins to the IM during their import. Finally, porins facilitate the transfer of lipids between the OM and IM and promote a back-up pathway for cardiolipin synthesis in mitochondria. Thus, porins have roles in addition to metabolite transport in mitochondria (Endo and Sakaue 2019). Δpor1 cells lacking VDAC1 show enhanced phospholipid biosynthesis, accumulate lipid droplets, increase vacuoles and cell size, and overproduce and excrete inositol (Magrì et al. 2019).

Using human VDAC as a template scaffold, Srivastava and Mahalakshmi 2020 designed and engineered odd- and even-stranded structures of smaller (V2(16), V2(17), V2(18)) and larger (V2(20), V2(21)) barrel diameters. Determination of the structures, dynamics, and energetics of these engineered structures in bilayer membranes revealed that the 19-stranded barrel holds modest to low stability, but possesses superior voltage-gated channel regulation, efficient mitochondrial targeting and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold.

The VDAC porin regulates the formation of the mitochondrial protein import gate in the OM, the translocase of the outer membrane (TOM) complex, and its dynamic exchange between the major form of a trimer and the minor form of a dimer. The TOM complex dimer lacks a core subunit Tom22 and mediates the import of a subset of mitochondrial proteins while the TOM complex trimer facilitates the import of most other mitochondrial proteins (Endo and Sakaue 2019). Porin also interacts with both a translocating inner membrane (IM) protein like a carrier protein accumulated at the small TIM chaperones in the intermembrane space and the TIM22 complex, a downstream translocator in the IM for the carrier protein import. Porin thereby facilitates the efficient transfer of carrier proteins to the IM during their import. Finally, porin facilitates the transfer of lipids between the OM and IM and promotes a back-up pathway for the cardiolipin synthesis in mitochondria (Endo and Sakaue 2019).

VDAC provides the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane (Rostovtseva et al. 2021). VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two   cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC's sensitivity to transmembrane potential is dramatically increased. The features of the VDAC gated states relevant to reduced metabolite flux and increased calcium flux are preserved in the blocked state induced by either docking protein (Rostovtseva et al. 2021).

The generalized transport reaction catalyzed by VDACs is:

(Anionic) metabolites (out) ↔ anionic metabolites (intermembrane space)



This family belongs to the Outer Membrane Pore-forming Protein I (OMPP-I) Superfamily .

 

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Song, J., C. Midson, E. Blachly-Dyson, M. Forte, and M. Colombini. (1998). The topology of VDAC as probed by biotin modification. J. Biol. Chem. 273: 24406-24413.

Specchia, V., F. Guarino, A. Messina, M.P. Bozzetti, and V. De Pinto. (2008). Porin isoform 2 has a different localization in Drosophila melanogaster ovaries than porin 1. J. Bioenerg. Biomembr. 40: 219-226.

Sridharan M., Bowles EA., Richards JP., Krantic M., Davis KL., Dietrich KA., Stephenson AH., Ellsworth ML. and Sprague RS. (2012). Prostacyclin receptor-mediated ATP release from erythrocytes requires the voltage-dependent anion channel. Am J Physiol Heart Circ Physiol. 302(3):H553-9.

Srivastava, S.R. and R. Mahalakshmi. (2020). Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance. J. Biol. Chem. [Epub: Ahead of Print]

Srivastava, S.R., P. Zadafiya, and R. Mahalakshmi. (2018). Hydrophobic Mismatch Modulates Stability and Plasticity of Human Mitochondrial VDAC2. Biophys. J. [Epub: Ahead of Print]

Teixeira, J., C. Oliveira, F. Cagide, R. Amorim, J. Garrido, F. Borges, and P.J. Oliveira. (2018). Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid. J Enzyme Inhib Med Chem 33: 567-576.

Troll, H., D. Malchow, A. Müller-Taubenberger, B. Humbel, F. Lottspeich, M. Ecke, G. Gerisch, A. Schmid, and R. Benz. (1992). Purification, functional characterization, and cDNA sequencing of mitochondrial porin from Dictyostelium discoideum. J. Biol. Chem. 267: 21072-21079.

Ujwal, R., D. Cascio, J.P. Colletier, S. Faham, J. Zhang, L. Toro, P. Ping, and J. Abramson. (2008). The crystal structure of mouse VDAC1 at 2.3 Å resolution reveals mechanistic insights into metabolite gating. Proc. Natl. Acad. Sci. USA 105: 17742-17747.

Unten, Y., M. Murai, T. Yamamoto, A. Watanabe, N. Ichimaru, S. Aburaya, W. Aoki, Y. Shinohara, and H. Miyoshi. (2019). Pentenediol-Type Compounds Specifically Bind to Voltage-Dependent Anion Channel 1 in Saccharomyces cerevisiae Mitochondria. Biochemistry 58: 1141-1154.

Verrier, F., A. Deniaud, M. Lebras, D. Métivier, G. Kroemer, B. Mignotte, G. Jan, and C. Brenner. (2004). Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis. Oncogene 23: 8049-8064.

Wojtkowska, M., M. Jąkalski, J.R. Pieńkowska, O. Stobienia, A. Karachitos, T.M. Przytycka, J. Weiner, 3rd, H. Kmita, and W. Makałowski. (2012). Phylogenetic analysis of mitochondrial outer membrane β-barrel channels. Genome Biol Evol 4: 110-125.

Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.

Xia, C., B. Fu, X. Zhang, C. Qin, and J.C. Jin. (2020). Chitosan quaternary ammonium salt induced mitochondrial membrane permeability transition pore opening study in a spectroscopic perspective. Int J Biol Macromol 165: 314-320. [Epub: Ahead of Print]

Yagoda N., M. von Rechenberg, E. Zaganjor, A.J. Bauer, W.S. Yang, D.J. Fridman, A.J. Wolpaw, I. Smukste, J.M. Peltier, J.J. Boniface, R. SmitH, S.L. Lessnick, S. Sahasrabudhe, B.R. Stockwell. (2007). RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 447: 864-868

Yehezkel, G., Hadad, N., Zaid, H., Sivan, S., and Shoshan-Barmatz, V. (2006). Nucleotide-binding sites in the voltage-dependent anion channel: characterization and localization. J. Biol. Chem. 281: 5938-5946.

Zeth, K. (2010). Structure and evolution of mitochondrial outer membrane proteins of β-barrel topology. Biochim. Biophys. Acta. 1797: 1292-1299.

Zhang, E., I. Mohammed Al-Amily, S. Mohammed, C. Luan, O. Asplund, M. Ahmed, Y. Ye, D. Ben-Hail, A. Soni, N. Vishnu, P. Bompada, Y. De Marinis, L. Groop, V. Shoshan-Barmatz, E. Renström, C.B. Wollheim, and A. Salehi. (2018). Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells. Cell Metab. [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
1.B.8.1.1

Voltage-dependent anion channel-1 (VDAC1; OMP2; Por1) porin.  It is a component of the mitochondrial permeability transition pore (mPTP) which includes cyclophilin D, VDAC and the adenine nucleotide translocator (TC subfamily 2.A.29.1) (Austin et al. 2013). Mitochondrial synthesis of cardiolipin (CL) and phosphatidylethanolamine requires the transport of their precursors, phosphatidic acid and phosphatidylserine, respectively, to the mitochondrial inner membrane. The Ups1-Mdm35 and Ups2-Mdm35 complexes transfer phosphatidic acid and phosphatidylserine, respectively, between the mitochondrial outer and inner membranes. A Ups1-independent CL accumulation pathway requires several mitochondrial proteins with unknown functions including Mdm31. Miyata et al. 2018 identified VDAC1 (Por1) as a protein that interacts with both Mdm31 and Mdm35. Depletion of the porins Por1 and Por2 destabilized Ups1 and Ups2, decreased CL levels by ~90%, and caused loss of Ups2-dependent phosphatidylethanolamine synthesis, but did not affect Ups2-independent phosphatidylethanolamine synthesis in mitochondria. Por1 mutations that affected its interactions with Mdm31 and Mdm35, but not respiratory growth, also decreased CL levels. Using HeLa cells, the authors showed that mammalian porins also function in mitochondrial CL metabolism. Thus, yeast porins function in mitochondrial phospholipid metabolism, and porin-mediated regulation of CL metabolism appears to be evolutionarily conserved. VDACs are targeted to mitocondria via a C-terminal hydrophobic β-strand terminated by a hydrophiic residue (Klinger et al. 2019). Pentenediol-type compounds bind to VDAC1 (Unten et al. 2019). VDACs play a major role in the mitochondrial permeability transition, and inhibition of the MPT improves bone fracture repair (Shares et al. 2020). Gallic acid inhibits the celecoxib-induced mitochondrial permeability transition and reduces its toxicity (Salimi et al. 2021).

Yeast, animals, plants

Mitochondrial outer membrane VDAC of Saccharomyces cerevisiae

 
1.B.8.1.10

Outer membrane porin, VDAC of 346 aas. This protein may function in the thylacoid membrane of the chloroplast as a non-selective voltage-indiependent porin (see TC# 1.B.8.8.7 and Kojima et al. 2018).

Red algae

VDAC of Galdieria sulphuraria

 
1.B.8.1.11

Porin, VDAC of 309 aas

Red algae

VDAC of Galdieria sulphuraria

 
1.B.8.1.12

Mitochondrial outer membrane voltage-dependent anion-selective channel protein 2, VDAC-2 of 294 aas.  Protein:micelle ratios and cysteine residues in the protein influence VDAC2 stability and unfolding rates (Maurya and Mahalakshmi 2014).  VDAC-2  performs a different subset of regulatory functions than VDAC1. It has anti-apoptotic features and contributes to gametogenesis.It may also regulate ROS, steroidogenesis and mitochondria-associated endoplasmic reticulum membrane regulatory pathways (Maurya and Mahalakshmi 2015).  Plays a role in mitochondrial import of Bak and tBid-induced apoptosis (Naghdi et al. 2015). VDAC2 plasticity and stability in the mitochondrial outer membrane are modulated by physical properties of the bilayer (Srivastava et al. 2018). VDAC1 and VDAC2 are overall, very similar, exhibiting similar dynamic behavior and conformational homogeneity (Eddy et al. 2019). Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies (Ramos et al. 2019). 

Animals

VDAC2 of Homo sapiens

 
1.B.8.1.13

Mitochondrial outer membrane porin, PorA or VDAC (Troll et al. 1992).

Slime molds

Mitochondrial outer membrane porin of Dictyostelium discoideum (Q01501)

 
1.B.8.1.14

Voltage-dependent anion-selective channel (VDAC) protein of 282 aas

Stramenopiles

VDAC of Albugo laibachii

 
1.B.8.1.15

VDAC1 of 276 aas, one of five isoforms.  A knock out mutation (Δvdac1) resulted in abnormal ovule formation during female gametogenesis, and both the mitochondrial transmembrane potential and ATP synthesis were reduced (Pan et al. 2014). Targeting and surface recognition of mitochondrial β-barrel proteins in yeast, humans and plants depends on the hydrophobicity of the last β-hairpin of the β-barrel, but the presence of a hydrophilic amino acid at the C-terminus of the penultimate β-strand is also required for mitochondrial targeting (Klinger et al. 2019). Kanwar et al. 2020 presented a comparative overview to provide an integrative picture of the interactions of VDAC with different proteins in both animals and plants.

Plants

VDAC1 of Arabidopsis thaliana

 
1.B.8.1.16

Voltage-dependent anion channel, VDAC, of 283 aas

VDAC of Paralichthys olivaceus (Bastard halibut) (Hippoglossus olivaceus)

 
1.B.8.1.17

Non-selective channel of the thylakoid membrane of 275 aas and one TMSs, CpTPOR (Kojima et al. 2018). The channels are large enough for permeation of small organic compounds (e.g. carbohydrates and amino acids with Mr < 1500). The pore has an estimated radius of ∼1.3 nm and exhibits a typical single-channel conductance of 1.8 nS in 1 m KCl with infrequent closing transitions. CpTPOR exhibits no obvious selectivity for anions and no voltage-dependent gating. It presumably enables rapid transfer of various metabolites between the lumen and stroma (Kojima et al. 2018).

TPOR of Cyanophora paradoxa chloroplasts (muroplasts)

 
1.B.8.1.18

VDAC2 of 281 aas, 1 N-terminal α-TMS and 19 β-TMSs.  Forms channels much like those of VDAC1 (Guardiani et al. 2018).

VDAC2 of Saccharomyces cerevisiae

 
1.B.8.1.19

Outer membrane porin, VDAC3 (HSR2) of 274 aas. This protein may function in the thylacoid membrane of the chloroplast as a non-selective voltage-indiependent porin (see TC# 1.B.8.8.7 and Kojima et al. 2018).

HSR2 of Arabidopsis thaliana (Mouse-ear cress)

 
1.B.8.1.2

VDAC3 porin.  The human orthologue forms small pores in membranes (Checchetto et al. 2014).  VDAC3 is a sensor of the oxidative state in the mitochondrial intermembrane space, and cysteyl residue modification appears to play a role (Reina et al. 2016). Post translational modifications of VDAC3 that can impact its protective role against reactive oxygen species (ROS), which is particularly important in the ALS context (Pittalà et al. 2022).

Yeast, animals, plants

Mitochondrial outer membrane VDAC3 of Mus musculus

 
1.B.8.1.20

Miltochondrial outer membrane porin, VDAC, of 283 aas. The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective. The absence of VDAC is associated with increased reactive oxygen species (ROS) production (Shuvo et al. 2019).

VDAC of Neurospora crassa

 
1.B.8.1.3

VDAC1, VDAC-1 or VDAC porin of 283 aas, which is > 99% identical to human (P21796) and mouse (60932) VDAC1. Mammals possess three VDACs (VDAC1, 2 and 3) encoded by three genes, but they are all similar in sequence (~60-70% identical) (Messina et al., 2011).  The 3-d structure of the human VDAC1 is known (PDB ID 2JK4; Bayrhuber et al. 2008).  Reviewed by Shoshan-Barmatz et al. 2015.  VDAC1 is found both in mitochondria and the plasma membrane (Lawen et al. 2005) where it may cause cytoplasmic ATP loss.. It may be involved in cancer (Shoshan-Barmatz et al. 2017) and Alzheimer's disease (AD) (Shoshan-Barmatz et al. 2018). Along with its low toxicity profile and high antioxidant activity, the gallic acid derivative, AntiOxBEN3, strongly inhibits calcium-dependent mitochondrial permeability transition pore (mPTP) opening (Teixeira et al. 2018). VDAC dimerization plays a role in mitochondrial metabolic regulation and apoptosis in response to cytosolic acidification during cellular stress, and E73 is involved (Bergdoll et al. 2018). Inhibiting VDAC1 overproduction and plasma membrane insertion in β-cells preserves insulin secretion in diabetes (Zhang et al. 2018). βII and βIII-tubulin, bound to VDAC, regulate VDAC permeability (Puurand et al. 2019). This VDAC porin interacts with carrier precursors arriving in the intermembrane space and recruits TIM22 complexes, thus ensuring efficient transfer of the precursors to the inner membrane translocase (Ellenrieder et al. 2019). A method has been develped to determine the number of VDAC1 channels (and other integral membrane proteins) in nanodiscs under various assembly conditions (Häusler et al. 2020). Stable low-conducting states of human VDAC1 predominantly take place from disordered events and do not result from the displacement of a voltage sensor or a significant change in the pore. Conductance jumps reveal entropy as a key factor for VDAC gating (Preto et al. 2022). The lysyl residue at position 12 in the pore interior is responsible for most of VDAC's voltage sensitivity (Ngo et al. 2022).  Oral administration of VDAC1-derived small peptides increases circulating testosterone levels in male rats (Martinez-Arguelles et al. 2022).

 

Yeast, animals, plants

Mitochondrial and plasma membrane VDAC of Bos taurus

 
1.B.8.1.4

VDAC porin.  The open state has a weak anion selectivity whereas the closed state is cation-selective.

Yeast, animals, plants Mitochondrial outer membrane VDAC of Triticum aestivum
 
1.B.8.1.5Non green plastid porin Plants Plastid porin of Pisum sativum
 
1.B.8.1.6

Voltage-dependent anion-selective porin1 (Porin-1, VDAC or Por-1) (De Pinto et al. 1989; Aiello et al., 2004) (one of three paralogues). Mutations in VDAC leads to neurologic dysfunction and male infertility in Drosophila  (Graham et al., 2010).  Porin 1 is abundantly expressed in both male and female germ cell tissues; Porin 2 is abundant in testis but in small amounts in ovaries. The immuno-histological stain of ovaries shows that Porin isoform 1 is selectively targeted to follicular cells while Porin isoform 2 is present in mitochondria of the epithelial sheath cells of the ovariole (Guarino et al. 2006; Specchia et al. 2008).

Animals

Porin 1 of Drosophila melanogaster
(Q94920)

 
1.B.8.1.7

Voltage-independent, cation-selective porin2 (Porin-2 or Por-2) (converted to anion selective by changing Glu-66 and Glu-163 to lysines; Aiello et al., 2004). One of three paralogues (Craigen and Graham, 2008).  Porin 1 is abundantly expressed in both male and female germ cell tissues; Porin 2 is abundant in testis but in small amounts in ovaries. The immuno-histological stain of ovaries shows that Porin 1 is selectively targeted to follicular cells while Porin 2 is present in mitochondria of the epithelial sheath cells of the ovariole (Specchia et al. 2008).

Animals

Porin 2 of Drosophila melanogaster
(Q9VKP2)

 
1.B.8.1.8

 

Rice VDAC4.  Channels formed in planar bilayers exhibit large conductance (4.6 ± 0.3 nS in 1 M KCl), strong voltage dependence and weak anion selectivity. The open state of the channel is  permeable to ATP (Godbole et al. 2011).

Plants

VDAC4 of Oryza sativa

 
1.B.8.1.9

Mitochondrial outer membrane porin, VDAC, of 292 aas (De Pinto et al. 1989).

Animals

VDAC of Drosophila melanogaster

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.2.1

19 β-stranded barrel translocase across the outer membrane, Tom40 (Pfam Porin 3 Superfamily).

Fungi

Tom40 of Saccharomyces cerevisiae

 
1.B.8.2.10

Porin protein of 368 aas

Alveolata (ciliate)

Porin protein of Tetrahymena thermophila

 
1.B.8.2.11

Putative porin of 284 aas

Fungi

Putative porin of Encephalitozoon cuniculi

 
1.B.8.2.12

Entamoeba histolytica, an anaerobic intestinal parasite causing dysentery and extra-intestinal abscesses in humans, possesses highly reduced and divergent mitochondrion-related organelles (MROs) called mitosomes. This organelle lacks many features associated with canonical aerobic mitochondria and even other MROs such as hydrogenosomes. The Entamoeba mitosome has been found to have a compartmentalized sulfate activation pathway, which has a role in amebic stage conversion. It also features a unique shuttle system that delivers proteins from the cytosol to the mitosome. Only Entamoeba mitosomes possess a novel subclass of β-barrel outer membrane protein called MBOMP30.The mitosome protein import complex consisting of at least two proteins, TOM40, which provides the channel, and TOM60, which seems to be necessary for protein import (Makiuchi et al. 2013; Santos et al. 2016).

TOM40/TOM60 of Entamoeba histolytica

 
1.B.8.2.13

TOM40 (377 aas)/TOM22 (105 aas)/TOM7 (66 aas) of the mitochondrial import receptor, 3 subunits (Wunderlich 2022).

TOM complex of Plasmodium falciparum

 
1.B.8.2.2

Tom40 of 344 aas

Animals

Tom40 of Drosophila melanogaster

 
1.B.8.2.3

Eukaryotic porin family, Tom40-2 of 310 aas

Plants

Tom40 of Arabidopsis thaliana

 
1.B.8.2.4

Tom40 of 361 aas

Amoebozoa

Tom40 of Acanthamoeba castellanii

 
1.B.8.2.5

Mitochondrial import receptor, Tom40 of 361 aas

Animals

Tom40 of Homo sapiens

 
1.B.8.2.6

Tom40 of 314 aas

Amoebozoa (slime molds)

Tom40 of Dictyostelium discoideum

 
1.B.8.2.7

Tom40 of 264 aas

Marine diatoms

Tom40 of Thalassiosira occanica

 
1.B.8.2.8

Tom40 of 301 aas

Animals

Tom40 of Caenorhabditis elegans

 
1.B.8.2.9

Mitochondrial import receptor, Tom40 of 394 aas

Alveolata

Tom40 of Plasmodium knowlesi

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.3.1

Putative mitochondrial porin of 309 aas (Porin3_VDAC superfamily)

Ciliates

MPP family member of Tetrahymena thermophila (Q22Z08)

 
1.B.8.3.2

Mitochondrial porin of 305aas (Porin3_VDAC superfamily).  Exhibits the properties of a voltage-dependent general diffusion porin with cation-selectivity and a pore diameter of 1.3 nm (Ludwig et al. 1989).

Ciliates

MPP family member of Paramecium tetraurelia (Q3SE03)

 
1.B.8.3.3

Putative mitochondrial porin of 301aas (Porin3_VDAC superfamily)

Ciliates

MPP family member of Oxytricha trifallax (J9JBL0)

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.4.1

VDAC homologue of 277 aas

Euglenozoa

VDAC of Leishmania mexicana

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.5.1

VDAC homologue

Alveolata

VDAC of Theileria orientalis

 
1.B.8.5.2

VDAC (OMPP) homologue of 289 aas and 0 TMSs.

Alveolata

VDAC of Plasmodium falciprarum

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.6.1

The Mdm10 protein of 493 aas, a putative eukaryotic porin.  It belongs to the eukaryotic porin 3 superfamily together with VDAC and Tom40 (Flinner et al. 2013).  This protein is also listed under TC# 1.B.33.3.1 and TC#9.B.58.1.1 as part of two complexes: the mitochondrial Sorting and Assembly Machinery (SAM) and the TULIP complex, respectively.

Fungi

Mdm10 of Saccharomyces cerevisiae

 
1.B.8.6.2

Mdm10 protein of 646 aas

corn smut fungi

Mdm10 of Ustilago maydis

 
1.B.8.6.3

Mdm10 protein of 317 aas

Amoebozoa

Mdm10 of Acanthamoeba castellanii

 
1.B.8.6.4

Uncharacterized protein of 323 aas

Amoebozoa; slime molds

Mdm10 of Dictyostelium discoideum

 
1.B.8.6.5

Uncharacterized protein of 435 aas

Fungi

UP of Pyrenophora tritici-repentis

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.7.1

Porin protein of 290 aas

Euglenozoa

Porin protein of Euglena gracilis

 
Examples:

TC#NameOrganismal TypeExample
1.B.8.8.1

Pore-forming β-barrel porin of 308 aas in hydrogenosomes, Tom40-1 (Makki et al. 2019).

Tom40-1 of Trichomonas vaginalis

 
1.B.8.8.2

Pore-forming β-barrel porin of 290 aas, present in hydrogenosomes, Tom40-2 (Makki et al. 2019).

Tom40-2 of Trichomonas vaginalis

 
1.B.8.8.3

Pore-forming β-barrel porin of 305 aas in hydrogenosomes, Tom40-3 (Makki et al. 2019).

Tom40-3 of Trichomonas vaginalis

 
1.B.8.8.4

Pore-forming β-barrel porin of 296 aas in hydrogenosomes, Tom40-4 (Makki et al. 2019).

Tom40-4 of Trichomonas vaginalis

 
1.B.8.8.5

Pore-forming β-barrel porin of 397 aas in hydrogenosomes, Tom40-5 (Makki et al. 2019).

Tom40-5 of Trichomonas vaginalis

 
1.B.8.8.6

Pore-forming β-barrel porin of 298 aas in hydrogenosomes, Tom40-6 (Makki et al. 2019).

Tom40-6 of Trichomonas vaginalis