Voltage-dependent anion channel 3 (VDAC3) mediates P. syringae induced ABA-SA signaling crosstalk in Arabidopsis thaliana.

Pathogen severely affects plant mitochondrial processes including respiration, however, the roles and mechanism of mitochondrial protein during the immune response remain largely unexplored. The interplay of plant hormone signaling during defense is an outcome of plant pathogen interaction. We recently discovered that the Arabidopsis calcineurin B-like interacting protein kinase 9 (AtCIPK9) interacts with the voltage-dependent anion channel 3 (AtVDAC3) and inhibits MV-induced oxidative damage. Here we report the characterization of AtVDAC3 in an antagonistic interaction pathway between abscisic acid (ABA) and salicylic acid (SA) signaling in Pseudomonas syringae -Arabidopsis interaction. In this study, we observed that mutants of AtVDAC3 were highly susceptible to Pseudomonas syringae infection as compared to the wild type (WT) Arabidopsis plants. Transcripts of VDAC3 and CIPK9 were inducible upon ABA application. Following pathogen exposure, expression analyses of ABA and SA biosynthesis genes indicated that the function of VDAC3 is required for isochorisimate synthase 1 (ICS1) expression but not for Nine-cis-epoxycaotenoid dioxygenase 3 (NCED3) expression. Despite the fact that vdac3 mutants had increased NCED3 expression in response to pathogen challenge, transcripts of ABA sensitive genes such as AtRD22 and AtRAB18 were downregulated even after exogenous ABA application. VDAC3 is required for ABA responsive genes expression upon exogenous ABA application. We also found that Pseudomonas syringae-induced SA signaling is downregulated in vdac3 mutants since overexpression of VDAC3 resulted in hyperaccumulation of Pathogenesis related gene1 (PR1) transcript. Interestingly, ABA application prior to P. syringae inoculation resulted in the upregulation of ABA responsive genes like Responsive to ABA18 (RAB18) and Responsive to dehydration 22 (RD22). Intriguingly, in the absence of AtVDAC3, Pst challenge can dramatically increase ABA-induced RD22 and RAB18 expression. Altogether our results reveal a novel Pathogen-SA-ABA interaction pathway in plants. Our findings show that ABA plays a significant role in modifying plant-pathogen interactions, owing to cross-talk with the biotic stress signaling pathways of ABA and SA.

Human VDAC pseudogenes: an emerging role for VDAC1P8 pseudogene in acute myeloid leukemia.

BACKGROUND: Voltage-dependent anion selective channels (VDACs) are the most abundant mitochondrial outer membrane proteins, encoded in mammals by three genes, VDAC1, 2 and 3, mostly ubiquitously expressed. As 'mitochondrial gatekeepers', VDACs control organelle and cell metabolism and are involved in many diseases. Despite the presence of numerous VDAC pseudogenes in the human genome, their significance and possible role in VDAC protein expression has not yet been considered. RESULTS: We investigated the relevance of processed pseudogenes of human VDAC genes, both in physiological and in pathological contexts. Using high-throughput tools and querying many genomic and transcriptomic databases, we show that some VDAC pseudogenes are transcribed in specific tissues and pathological contexts. The obtained experimental data confirm an association of the VDAC1P8 pseudogene with acute myeloid leukemia (AML). CONCLUSIONS: Our in-silico comparative analysis between the VDAC1 gene and its VDAC1P8 pseudogene, together with experimental data produced in AML cellular models, indicate a specific over-expression of the VDAC1P8 pseudogene in AML, correlated with a downregulation of the parental VDAC1 gene.

Enteroviral 2B Interacts with VDAC3 to Regulate Reactive Oxygen Species Generation That Is Essential to Viral Replication.

Enterovirus (EV) 71 caused episodes of outbreaks in China and Southeast Asia during the last few decades. We have previously reported that EV71 induces reactive oxygen species (ROS). However, the underlying mechanism remains elusive. Co-immunoprecipitation-proteomic analysis revealed that enteroviral 2B protein interacted with mitochondrial voltage-dependent anion channel 3 (VDAC3). Knockdown (KD) of VDAC3 expression specifically inhibited enteroviral replication. Single-round viral replication was also inhibited in KD cells, suggesting that VDAC3 plays an essential role in replication. Consistent with this, VDAC3 gene KD significantly reduced the EV71-induced mitochondrial ROS generation. Exogenous 2B expression could induce the mitochondrial ROS generation that was significantly reduced in VDAC3-KD cells or in the Mito-TEMPO-treated cells. Moreover, VDAC3 appears to be necessary for regulation of antioxidant metabolism. VDAC3 gene KD led to the enhancement of such pathways as hypotaurine/taurine synthesis in the infected cells. Taken together, these findings suggest that 2B and VDAC3 interact to enhance mitochondrial ROS generation, which promotes viral replication.

The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination.

Ferroptosis is a novel form of cell death that is closely associated with the formation of many tumors. Our study focused on the mechanism by which long noncoding RNAs (lncRNAs) regulate ferroptosis in gastric cancer (GC) peritoneal metastasis (PM). We utilized lncRNA sequencing and protein profiling analysis to identify ferroptosis-associated lncRNAs and proteins. qRT-PCR was used to analyze the expression of BDNF-AS and FBXW7 in GC tissues and adjacent normal tissues. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and coimmunoprecipitation (co-IP) assays were performed to investigate the interaction between BDNF-AS and its downstream targets. Finally, the function of BDNF-AS was validated in vivo . We demonstrated that BDNF-AS was highly expressed in GC and PM tissues. High BDNF-AS expression was positively related to GC progression and poor prognosis. Functionally, BDNF-AS overexpression protected GC cells from ferroptosis and promoted the progression of GC and PM. Mechanistically, BDNF-AS could regulate FBXW7 expression by recruiting WDR5, thus affecting FBXW7 transcription, and FBXW7 regulated the protein expression of VDAC3 through ubiquitination. Conclusively, our research demonstrated that the BDNF-AS/WDR5/FBXW7 axis regulates ferroptosis in GC by affecting VDAC3 ubiquitination. BDNF-AS might be a biomarker for the evaluation of GC prognosis and the treatment of GC.

Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis.

Although several long noncoding RNAs (lncRNAs) have recently been shown to encode small polypeptides, those in testis remain largely uncharacterized. Here we identify two sperm-specific polypeptides, Kastor and Polluks, encoded by a single mouse locus (Gm9999) previously annotated as encoding a lncRNA. Both Kastor and Polluks are inserted in the outer mitochondrial membrane and directly interact with voltage-dependent anion channel (VDAC), despite their different amino acid sequences. Male VDAC3-deficient mice are infertile as a result of reduced sperm motility due to an abnormal mitochondrial sheath in spermatozoa, and deficiency of both Kastor and Polluks also severely impaired male fertility in association with formation of a similarly abnormal mitochondrial sheath. Spermatozoa lacking either Kastor or Polluks partially recapitulate the phenotype of those lacking both. Cooperative function of Kastor and Polluks in regulation of VDAC3 may thus be essential for mitochondrial sheath formation in spermatozoa and for male fertility.

Voltage Dependent Anion Channel 3 (VDAC3) protects mitochondria from oxidative stress.

Unraveling the role of VDAC3 within living cells is challenging and still requires a definitive answer. Unlike VDAC1 and VDAC2, the outer mitochondrial membrane porin 3 exhibits unique biophysical features that suggest unknown cellular functions. Electrophysiological studies on VDAC3 carrying selective cysteine mutations and mass spectrometry data about the redox state of such sulfur containing amino acids are consistent with a putative involvement of isoform 3 in mitochondrial ROS homeostasis. Here, we thoroughly examined this issue and provided for the first time direct evidence of the role of VDAC3 in cellular response to oxidative stress. Depletion of isoform 3 but not isoform 1 significantly exacerbated the cytotoxicity of redox cyclers such as menadione and paraquat, and respiratory complex I inhibitors like rotenone, promoting uncontrolled accumulation of mitochondrial free radicals. High-resolution respirometry of transiently transfected HAP1-ΔVDAC3 cells expressing the wild type or the cysteine-null mutant VDAC3 protein, unequivocally confirmed that VDAC3 cysteines are indispensable for protein ability to counteract ROS-induced oxidative stress.

Characterization of the voltage-dependent anion channel (VDAC) gene family in wheat (Triticum aestivum L.) and its potential mechanism in response to drought and salinity stresses.

Voltage-dependent anion channels (VDACs) are major transport proteins localized in the outer membrane of mitochondria and play critical roles in regulating plant growth and responding to stress. In this study, a total of 26 VDAC genes in common wheat (Triticum aestivum L.) were identified. TaVDACs that contained ß-barrel structures were classified into three groups with phylogenetic and sequence alignment. Additionally, the gene structure and protein conserved motif composition varied among diverse subfamilies but were relatively conserved within the same subfamily. The basic elements that were stress- and hormone-related, including TATA-box, CAAT-box, MBS, LTR, TC-rich repeats, ABRE, P-box and TATC-box, were predicted within the promoter region of TaVDAC genes. TaVDAC expression patterns differed among tissues, organs and abiotic stress conditions. Overexpression (OE) of TaVDAC1-B conferred high tolerance to salinity and less resistance to drought stress in Arabidopsis thaliana. TaVDAC1-B interacted with Nucleoredoxin-D1 (TaNRX-D1) protein. Furthermore, compared with WT lines, salinity stress further upregulated the level of AtNRX1 (homologous gene of TaNRX-D1 in Arabidopsis) expression and the activity of superoxide dismutase in TaVDAC1-B OE lines, which led to a decrease in superoxide radical accumulation; drought stress further downregulated AtNRX1 expression and superoxide dismutase activity in TaVDAC1-B OE lines, resulting in the accumulation of superoxide radicals. Our study not only presents comprehensive information for understanding the VDAC gene family in wheat but also proposes a potential mechanism in response to drought and salinity stress.

CIPK9 targets VDAC3 and modulates oxidative stress responses in Arabidopsis.

Calcium (Ca2+ ) is widely recognized as a key second messenger in mediating various plant adaptive responses. Here we show that calcineurin B-like interacting protein kinase CIPK9 along with its interacting partner VDAC3 identified in the present study are involved in mediating plant responses to methyl viologen (MV). CIPK9 physically interacts with and phosphorylates VDAC3. Co-localization, co-immunoprecipitation, and fluorescence resonance energy transfer experiments proved their physical interaction in planta. Both cipk9 and vdac3 mutants exhibited a tolerant phenotype against MV-induced oxidative stress, which coincided with the lower-level accumulation of reactive oxygen species in their roots. In addition, the analysis of cipk9vdac3 double mutant and VDAC3 overexpressing plants revealed that CIPK9 and VDAC3 were involved in the same pathway for inducing MV-dependent oxidative stress. The response to MV was suppressed by the addition of lanthanum chloride, a non-specific Ca2+ channel blocker indicating the role of Ca2+ in this pathway. Our study suggest that CIPK9-VDAC3 module may act as a key component in mediating oxidative stress responses in Arabidopsis.

Overexpression of a Voltage-Dependent Anion-Selective Channel (VDAC) Protein-Encoding Gene, MsVDAC, from Medicago sativa Confers Cold and Drought Tolerance to Transgenic Tobacco.

Voltage-dependent anion channels (VDACs) are highly conserved proteins that are involved in the translocation of tRNA and play a key role in modulating plant senescence and multiple pathways. However, the functions of VDACs in plants are still poorly understood. Here, a novel VDAC gene was isolated and identified from alfalfa (Medicago sativa L.). MsVDAC localized to the mitochondria, and its expression was highest in alfalfa roots and was induced in response to cold, drought and salt treatment. Overexpression of MsVDAC in tobacco significantly increased MDA, GSH, soluble sugars, soluble protein and proline contents under cold and drought stress. However, the activities of SOD and POD decreased in transgenic tobacco under cold stress, while the O2- content increased. Stress-responsive genes including LTP1, ERD10B and Hxk3 were upregulated in the transgenic plants under cold and drought stress. However, GAPC, CBL1, BI-1, Cu/ZnSOD and MnSOD were upregulated only in the transgenic tobacco plants under cold stress, and GAPC, CBL1, and BI-1 were downregulated under drought stress. These results suggest that MsVDAC provides cold tolerance by regulating ROS scavenging, osmotic homeostasis and stress-responsive gene expression in plants, but the improved drought tolerance via MsVDAC may be mainly due to osmotic homeostasis and stress-responsive genes.

Depletion of a Toxoplasma porin leads to defects in mitochondrial morphology and contacts with the endoplasmic reticulum.

The voltage-dependent anion channel (VDAC) is a ubiquitous channel in the outer membrane of the mitochondrion with multiple roles in protein, metabolite and small molecule transport. In mammalian cells, VDAC protein, as part of a larger complex including the inositol triphosphate receptor, has been shown to have a role in mediating contacts between the mitochondria and endoplasmic reticulum (ER). We identify VDAC of the pathogenic apicomplexan Toxoplasma gondii and demonstrate its importance for parasite growth. We show that VDAC is involved in protein import and metabolite transfer to mitochondria. Further, depletion of VDAC resulted in significant morphological changes in the mitochondrion and ER, suggesting a role in mediating contacts between these organelles in T. gondii. This article has an associated First Person interview with the first author of the paper.

HSP70-16 and VDAC3 jointly inhibit seed germination under cold stress in Arabidopsis.

Abscisic acid (ABA) transport plays a crucial role in seed germination under unfavourable conditions such as cold stress. Both heat shock protein 70 (HSP70) and voltage-dependent anion channel (VDAC) protein are involved in cold stress responses in Arabidopsis. However, their roles in seed germination with regard to ABA signaling remain unknown. Here we demonstrated that Arabidopsis HSP70-16 and VDAC3 jointly suppress seed germination under cold stress conditions. At 4°C, both HSP70-16 and VDAC3 facilitated the efflux of ABA from the endosperm to the embryo and thus inhibited seed germination. HSP70-16 interacted with VDAC3 on the plasma membrane and in the nucleus, and the interplay between HSP70-16 and VDAC3 activated the opening of the VDAC3 ion channel. Our work established a novel function of HSP70-16 in seed germination under cold stress and a possible association of VDAC3 activity with ABA transportation from endosperm to embryo under cold stress conditions. This study reveals that HSP70-16 interacts with VDAC3 and facilitates the opening of the VDAC3 ion channel, which influences ABA efflux from endosperm to embryo, thus negatively regulates seed germination under cold stress.

NDRG1 regulates osteosarcoma cells via mediating the mitochondrial function and CSCs differentiation.

BACKGROUND: Cancer stem cells (CSCs) are mainly contributed to malignancy metastatic potential and resistant therapy of osteosarcoma (OS). The mitochondria-related apoptosis was generally accepted as the target of tumor therapy. However, the effect of N-myc downstream-regulated gene 1 (NDRG1) on CSCs and mitochondrial health in OS is still unknown. METHODS: In OS cells, MG63 and U2OS, the siRNA of NDRG1 were conducted. Transwell, western blot, RT-qPCR, and mitochondria isolation were used to identify the effect of NDRG on OS cells and mitochondria. Moreover, the differentiation-related factors of CSCs were determined. RESULTS: After downregulation of NDRG1, the cell viability, invasion ability decreased whereas cell apoptosis increased. The expressions profiles of fibronectin, vimentin, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP) 2, MMP9, and MMP13 were downregulated, but E-cadherin expression level was upregulated by NDRG1 siRNA. At the same time, cytochrome (Cyt) C levels were increased in cytosol with the decreasing in mitochondria after siRNA treatment. The mitochondrial membrane potential (MMPs) was declined, and the function of mitochondria was impeded. The expressions of uncoupling proteins (UCP) 2, voltage dependent anion channel (VDAC), peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, and cyclooxygenase (COX) 2 were downregulated by NDRG1 silencing. Moreover, NDRG performed its function primarily through the Wnt pathway and could regulate the differentiation of osteosarcoma stem cells. CONCLUSION: Silencing of NDRG1 could damage the function of mitochondria, promote the CSCs differentiation, alleviating OS progression.

Identification and Expression Analysis of SLAC/SLAH Gene Family in Brassica napus L.

Slow type anion channels (SLAC/SLAHs) play important roles during anion transport, growth and development, abiotic stress responses and hormone responses in plants. However, there is few report on SLAC/SLAHs in rapeseed (Brassica napus). Genome-wide identification and expression analysis of SLAC/SLAH gene family members were performed in B. napus. A total of 23 SLAC/SLAH genes were identified in B. napus. Based on the structural characteristics and phylogenetic analysis of these members, the SLAC/SLAHs could be classified into three main groups. Transcriptome data demonstrated that BnSLAH3 genes were detected in various tissues of the rapeseed and could be up-regulated by low nitrate treatment in roots. BnSLAC/SLAHs were exclusively localized on the plasma membrane in transient expression of tobacco leaves. These results will increase our understanding of the evolution and expression of the SLAC/SLAHs and provide evidence for further research of biological functions of candidates in B. napus.

ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility.

The mammalian sperm midpiece has a unique double-helical structure called the mitochondrial sheath that wraps tightly around the axoneme. Despite the remarkable organization of the mitochondrial sheath, the molecular mechanisms involved in mitochondrial sheath formation are unclear. In the process of screening testis-enriched genes for functions in mice, we identified armadillo repeat-containing 12 (ARMC12) as an essential protein for mitochondrial sheath formation. Here, we engineered Armc12-null mice, FLAG-tagged Armc12 knock-in mice, and TBC1 domain family member 21 (Tbc1d21)-null mice to define the functions of ARMC12 in mitochondrial sheath formation in vivo. We discovered that absence of ARMC12 causes abnormal mitochondrial coiling along the flagellum, resulting in reduced sperm motility and male sterility. During spermiogenesis, sperm mitochondria in Armc12-null mice cannot elongate properly at the mitochondrial interlocking step which disrupts abnormal mitochondrial coiling. ARMC12 is a mitochondrial peripheral membrane protein and functions as an adherence factor between mitochondria in cultured cells. ARMC12 in testicular germ cells interacts with mitochondrial proteins MIC60, VDAC2, and VDAC3 as well as TBC1D21 and GK2, which are required for mitochondrial sheath formation. We also observed that TBC1D21 is essential for the interaction between ARMC12 and VDAC proteins in vivo. These results indicate that ARMC12 uses integral mitochondrial membrane proteins VDAC2 and VDAC3 as scaffolds to link mitochondria and works cooperatively with TBC1D21. Thus, our studies have revealed that ARMC12 regulates spatiotemporal mitochondrial dynamics to form the mitochondrial sheath through cooperative interactions with several proteins on the sperm mitochondrial surface.

An improved method for precise genome editing in zebrafish using CRISPR-Cas9 technique.

Current methods of CRISPR-Cas9-mediated site-specific mutagenesis create deletions and small insertions at the target site which are repaired by imprecise non-homologous end-joining. Targeting of the Cas9 nuclease relies on a short guide RNA (gRNA) corresponding to the genome sequence approximately at the intended site of intervention. We here propose an improved version of CRISPR-Cas9 genome editing that relies on two complementary guide RNAs instead of one. Two guide RNAs delimit the intervention site and allow the precise deletion of several nucleotides at the target site. As proof of concept, we generated heterozygous deletion mutants of the kcng4b, gdap1, and ghitm genes in the zebrafish Danio rerio using this method. A further analysis by high-resolution DNA melting demonstrated a high efficiency and a low background of unpredicted mutations. The use of two complementary gRNAs improves CRISPR-Cas9 specificity and allows the creation of predictable and precise mutations in the genome of D. rerio.

Renaissance of VDAC: New Insights on a Protein Family at the Interface between Mitochondria and Cytosol.

It has become impossible to review all the existing literature on Voltage-Dependent Anion selective Channel (VDAC) in a single article. A real Renaissance of studies brings this protein to the center of decisive knowledge both for cell physiology and therapeutic application. This review, after highlighting the similarities between the cellular context and the study methods of the solute carriers present in the inner membrane and VDAC in the outer membrane of the mitochondria, will focus on the isoforms of VDAC and their biochemical characteristics. In particular, the possible reasons for their evolutionary onset will be discussed. The variations in their post-translational modifications and the differences between the regulatory regions of their genes, probably the key to understanding the current presence of these genes, will be described. Finally, the situation in the higher eukaryotes will be compared to that of yeast, a unicellular eukaryote, where there is only one active isoform and the role of VDAC in energy metabolism is better understood.

A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?

Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.

Kidney-disease-associated variants of Apolipoprotein L1 show gain of function in cation channel activity.

Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles.

Is the secret of VDAC Isoforms in their gene regulation? Characterization of human VDAC genes expression profile, promoter activity, and transcriptional regulators.

VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs' presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon-intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1-3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.

System biology analysis reveals the role of voltage-dependent anion channel in mitochondrial dysfunction during non-alcoholic fatty liver disease progression into hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatocellular carcinoma (HCC), but the underlying mechanisms behind the correlation of NAFLD with HCC are unclear. We aimed to uncover the genes and potential mechanisms that drive this progression. This study uncovered the genes and potential mechanisms through a multiple 'omics integration approach. Quantitative proteomics combined with phenotype-association analysis was performed. To investigate the potential mechanisms, a comprehensive transcriptome/lipidome/phenome-wide association analysis was performed in genetic reference panel BXD mice strains. The quantitative proteomics combined with phenotype-association results showed that VDAC1 was significantly increased in tumor tissues and correlated with NAFLD-related traits. Gene co-expression network analysis indicated that VDAC1 is involved in mitochondria dysfunction in the tumorigenic/tumor progression. The association between VDAC1 and mitochondria dysfunction can be explained by the fact that VDAC1 was associated with mitochondria membrane lipids cardiolipin (CL) composition shift. VDAC1 was correlated with the suppression of mature specie CL(LLLL) and elevation level of nascent CL species. Such profiling shift was supported by the significant positive correlation between VDAC1 and PTPMT1, as well as negative correlation with CL remodeling enzyme Tafazzin (TAZ). This study confirmed that the expression of VADC1 was dysregulated in NAFLD-driven HCC and associated with NAFLD progression. The VDAC1-driven mitochondria dysfunction is associated with cardiolipin composition shift, which causes alteration of mitochondria membrane properties.