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In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.

Mitophagy is a form of autophagy that selectively removes damaged mitochondria and attenuates mitochondrial-dependent apoptosis during viral infection, but how arboviruses balance mitophagy and apoptosis to facilitate persistent viral infection in insect vectors without causing evident fitness cost remains elusive. Here, we identified mitochondrial VDAC1 (voltage-dependent anion channel 1) that could be hijacked by nonstructural protein Pns11 of rice gall dwarf virus (RGDV), a plant nonenveloped double-stranded RNA virus, to synergistically activate pro-viral extensive mitophagy and limited apoptosis in leafhopper vectors. The direct target of fibrillar structures constructed by Pns11 with VDAC1 induced mitochondrial degeneration. Moreover, the degenerated mitochondria were recruited into Pns11-induced phagophores to initiate mitophagy via interaction of VDAC1 with Pns11 and an autophagy protein, ATG8. Such mitophagy mediated by Pns11 and VDAC1 required the classical PRKN/Parkin-PINK1 pathway. VDAC1 regulates apoptosis by controlling the release of apoptotic signaling molecules through its pore, while the anti-apoptotic protein GSN (gelsolin) could bind to VDAC1 pore. We demonstrated that the interaction of Pns11 with VDAC1 and gelsolin decreased VDAC1 expression but increased GSN expression, which prevented the extensive apoptotic response in virus-infected regions. Meanwhile, virus-induced mitophagy also effectively prevented extensive apoptotic response to decrease apoptosis-caused insect fitness cost. The subsequent fusion of virus-loaded mitophagosomes with lysosomes is prevented, and thus such mitophagosomes are exploited for persistent spread of virions within insect bodies. Our results reveal a new strategy for arboviruses to balance and exploit mitophagy and apoptosis, resulting in an optimal intracellular environment for persistent viral propagation in insect vectors. Abbreviations: ATG: autophagy related; BNIP3: BCL2 interacting protein 3; CYCS/CytC: cytochrome c, somatic; dsGSN: double-stranded RNAs targeting GSN/gelsolin; dsGFP: double-stranded RNAs targeting green fluorescent protein; dsPRKN: double-stranded RNAs targeting PRKN; dsPns11: double-stranded RNAs targeting Pns11; dsRNA: double-stranded RNA; EC: epithelia cell; GST: glutathione S-transferase; LAMP1: lysosomal associated membrane protein 1; Mito: mitochondrion; Mmg: middle midgut; MP, mitophagosome; PG, phagophore. padp: post-first access to diseased plants; PINK1: PTEN induced kinase 1; RGDV: rice gall dwarf virus; SQSTM1: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VDAC1: voltage dependent anion channel 1. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 ^M for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKa1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dor-somorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimu-lated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species (ROS) homeostasis. It is a key player in multiple human maladies including diabetes, cancer, neurodegeneration, and Parkinson's diseases. In healthy cells, mitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins in a process that could be altered by drugs or during illness. Here, we report that mitoNEET regulates the outer-mitochondrial membrane (OMM) protein voltage-dependent anion channel 1 (VDAC1). VDAC1 is a crucial player in the cross talk between the mitochondria and the cytosol. VDAC proteins function to regulate metabolites, ions, ROS, and fatty acid transport, as well as function as a "governator" sentry for the transport of metabolites and ions between the cytosol and the mitochondria. We find that the redox-sensitive [2Fe-2S] cluster protein mitoNEET gates VDAC1 when mitoNEET is oxidized. Addition of the VDAC inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) prevents both mitoNEET binding in vitro and mitoNEET-dependent mitochondrial iron accumulation in situ. We find that the DIDS inhibitor does not alter the redox state of MitoNEET. Taken together, our data indicate that mitoNEET regulates VDAC in a redox-dependent manner in cells, closing the pore and likely disrupting VDAC's flow of metabolites.

Voltage-dependent anion channel-1 (VDAC1) is a mitochondrial porin that is implicated in cellular metabolism and apoptosis, and modulated by numerous small molecules including lipids. VDAC1 binds sterols, including cholesterol and neurosteroids such as allopregnanolone. Biochemical and computational studies suggest that VDAC1 binds multiple cholesterol molecules, but photolabeling studies have identified only a single cholesterol and neurosteroid binding site at E73. To identify all the binding sites of neurosteroids in VDAC1, we apply photo-affinity labeling using two sterol-based photolabeling reagents with complementary photochemistry: 5α-6-AziP which contains an aliphatic diazirine, and KK200 which contains a trifluoromethyl-phenyldiazirine (TPD) group. 5α-6-AziP and KK200 photolabel multiple residues within an E73 pocket confirming the presence of this site and mapping sterol orientation within this pocket. In addition, KK200 photolabels four other sites consistent with the finding that VDAC1 co-purifies with five cholesterol molecules. Both allopregnanolone and cholesterol competitively prevent photolabeling at E73 and three other sites indicating that these are common sterol binding sites shared by both neurosteroids and cholesterol. Binding at the functionally important residue E73 suggests a possible role for sterols in regulating VDAC1 signaling and interaction with partner proteins.

Abstract Objective To investigate the effect of lidocaine on the expression of voltage-dependent anion channel 1 (VDAC1) in breast invasive carcinoma (BRCA) and its impact on the apoptosis of breast cancer cells. Methods We collected clinical data from patients with invasive breast cancer from 2010 to 2020 in the First affiliated hospital of Nanchang University, evaluated the prognostic value of VDAC1 gene expression in breast cancer, and detected the expression of VDAC1 protein in breast cancer tissues and paracancerous tissues by immunohistochemical staining of paraffin sections. Also, we cultured breast cancer cells (MCF-7) to observe the effect of lidocaine on the apoptosis of MCF-7 cells. Results Analysis of clinical data and gene expression data of BRCA patients showed VDAC1 was a differentially expressed gene in BRCA, VDAC1 may be of great significance for the diagnosis and prognosis of BRCA patients. Administration of lidocaine 3 mM significantly decreased VDAC1 expression, the expression of protein Bcl-2 was significantly decreased (p

Background & Aims: Chronic HCV infection causes cellular stress, fibrosis and predisposes to hepatocarcinogenesis. Mitochondria play key roles in orchestrating stress responses by regulating bioenergetics, inflammation and apoptosis. To better understand the role of mitochondria in the viral life cycle and disease progression of chronic hepatitis C, we studied morphological and functional mitochondrial alterations induced by HCV using productively infected hepatoma cells and patient livers. Methods: Biochemical and imaging assays were used to assess localization of cellular and viral proteins and mitochondrial functions in cell cultures and liver biopsies. Cyclophilin D (CypD) knockout was performed using CRISPR/Cas9 technology. Viral replication was quantified by quantitative reverse-transcription PCR and western blotting. Results: Several HCV proteins were found to associate with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), the points of contact between the ER and mitochondria. Downregulation of CypD, which is known to disrupt MAM integrity, reduced viral replication, suggesting that MAMs play an important role in the viral life cycle. This process was rescued by ectopic CypD expression. Furthermore, HCV proteins were found to associate with voltage dependent anion channel 1 (VDAC1) at MAMs and to reduce VDAC1 protein levels at MAMs in vitro and in patient biopsies. This association did not affect MAM-associated functions in glucose homeostasis and Ca2+ signaling. Conclusions: HCV proteins associate specifically with MAMs and MAMs play an important role in viral replication. The association between viral proteins and MAMs did not impact Ca2+ signaling between the ER and mitochondria or glucose homeostasis. Whether additional functions of MAMs and/or VDAC are impacted by HCV and contribute to the associated pathology remains to be assessed. Impact and implications: Hepatitis C virus infects the liver, where it causes inflammation, cell damage and increases the long-term risk of liver cancer. We show that several HCV proteins interact with mitochondria in liver cells and alter the composition of mitochondrial subdomains. Importantly, HCV requires the architecture of these mitochondrial subdomains to remain intact for efficient viral replication.

• VDAC1 is deeply involved in the toxic effect of environmental pollutants. • Association of VDAC1 monomers and oligomers with T2D. • VDAC1 affects insulin secretion and insulin resistance. • VDAC1 plays a bridging role in organelle crosstalk. • VDAC1 is a potential target for the prevention of pollutants-related T2D. Type 2 diabetes (T2D) is a chronic metabolic disease that accounts for more than 90% of diabetic patients. Its main feature is hyperglycemia due to insulin resistance or insulin deficiency. With changes in diet and lifestyle habits, the incidence of T2D in adolescents has burst in recent decades. The deterioration in the exposure to the environmental pollutants further aggravates the prevalence of T2D, and consequently, it imposes a significant economic burden. Therefore, early prevention and symptomatic treatment are essential to prevent diabetic complications. Mitochondrial number and electron transport chain activity are decreased in the patients with T2D. Voltage-Dependent Anion Channel 1 (VDAC1), as a crucial channel protein on the outer membrane of mitochondria, regulates signal transduction between mitochondria and other cellular components, participating in various biological processes. When VDAC1 exists in oligomeric form, it additionally facilitates the entry and exit of macromolecules into and from mitochondria, modulating insulin secretion. We summarize and highlight the interplay between VDAC1 and T2D, especially in the environmental pollutants-related T2D, shed light on the potential therapeutic implications of targeting VDAC1 monomers and oligomers, providing a new possible target for the treatment of T2D. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP)‐based chemotherapy is a preferred treatment for a broad spectrum of cancers, but the precise mechanisms of its hepatotoxicity are not yet clear. Recently, the role of voltage‐dependent anion channel protein 1 (VDAC1) in mitochondrial activity and cell apoptosis has attracted much attention. Our aim was to investigate the effects of mitochondrial outer membrane protein VDAC1 oligomerization in DDP‐induced hepatocyte apoptosis. L‐02 hepatocytes were divided into 4 groups: (a) control group, (b) 4,4'diisothiocyanate‐2,2'‐disulfonic acid (DIDS; 40 μm) group, (c) DDP (5 μm) group, and (d) DDP and DIDS combination group. Cell apoptosis was tested by Annexin V/FITC assay, protein expression of caspase‐3, γH2AX and NDUFB6 were observed by western blot assay, reactive oxygen species (ROS), and mitochondrial superoxide anion radical (O2•−) were detected by DCFH‐DA and MitoSOX probe, and DNA damage was assessed by comet assay. Moreover, the activity of mitochondrial respiratory chain complex I was determined by the colorimetry method. Compared with the control group, apoptosis rate and activated cleaved‐caspase‐3 protein, ROS and O2•− generation, DNA damage marker comet tail length, and γH2AX protein level increased in the DDP treatment group (P

The voltage-dependent anion channel (VDAC) is the most abundant protein in the outer mitochondrial membrane and constitutes the primary pathway for the exchange of ions and metabolites between the cytosol and the mitochondria. There is accumulating evidence supporting VDAC's role in mitochondrial metabolic regulation and apoptosis, where VDAC oligomerization has been implicated with these processes. Herein, we report a specific pH-dependent dimerization of murine VDAC1 (mVDAC1) identified by double electron-electron resonance and native mass spectrometry. Intermolecular distances on four singly spin-labeled mVDAC1 mutants were used to generate a model of the low-pH dimer, establishing the presence of residue E73 at the interface. This dimer arrangement is different from any oligomeric state previously described, and it forms as a steep function of pH with an apparent pKa of 7.4. Moreover, the monomer-dimer equilibrium affinity constant was determined using native MS, revealing a nearly eightfold enhancement in dimerization affinity at low pH. Mutation of E73 to either alanine or glutamine severely reduces oligomerization, demonstrating the role of protonated E73 in enhancing dimer formation. Based on these results, and the known importance of E73 in VDAC physiology, VDAC dimerization likely plays a significant role in mitochondrial metabolic regulation and apoptosis in response to cytosolic acidification during cellular stress.

Objective: To investigate the effect of lidocaine on the expression of voltage-dependent anion channel 1 (VDAC1) in breast invasive carcinoma (BRCA) and its impact on the apoptosis of breast cancer cells. Methods: We collected clinical data from patients with invasive breast cancer from 2010 to 2020 in the First affiliated hospital of Nanchang University, evaluated the prognostic value of VDAC1 gene expression in breast cancer, and detected the expression of VDAC1 protein in breast cancer tissues and paracancerous tissues by immunohistochemical staining of paraffin sections. Also, we cultured breast cancer cells (MCF-7) to observe the effect of lidocaine on the apoptosis of MCF-7 cells. Results: Analysis of clinical data and gene expression data of BRCA patients showed VDAC1 was a differentially expressed gene in BRCA, VDAC1 may be of great significance for the diagnosis and prognosis of BRCA patients. Administration of lidocaine 3 mM significantly decreased VDAC1 expression, the expression of protein Bcl-2 was significantly decreased (p < 0.05), and the expression of p53 increased significantly (p < 0.05). Lidocaine inhibited the proliferation of MCF-7 breast cancer cells, increased the percentage of G2 / M phase cells and apoptosis. Conclusion: Lidocaine may inhibit the activity of breast cancer cells by inhibiting the expression of VDAC1, increasing the apoptosis in breast cancer cells. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age‐dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P‐Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage‐dependent anion channel 1 (VDAC1) protein on mitophagy/autophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimer's disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with TAU mice and generated double mutant (VDAC1+/−/TAU) mice. We assessed phenotypic behavior, protein levels of mitophagy, autophagy, synaptic, other key proteins, mitochondrial morphology, and dendritic spines in TAU mice relative to double mutant mice. Partial reduction of VDAC1 rescued the TAU‐induced behavioral impairments such as motor coordination and exploratory behavioral changes, and learning and spatial memory impairments in VDAC1+/−/TAU mice. Protein levels of mitophagy, autophagy, and synaptic proteins were significantly increased in double mutant mice compared with TAU mice. In addition, dendritic spines were significantly increased; the mitochondrial number was significantly reduced, and mitochondrial length was increased in double mutant mice. Based on these observations, we conclude that reduced VDAC1 is beneficial in symptomatic‐transgenic TAU mice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common forms of neurodegeneration, defined by reduced cognitive function, which is caused by the gradual death of neurons in the brain. Recent studies have shown an age-dependent rise in the levels of voltage-dependent anion channel 1 (VDAC1) in AD. In addition, we discovered an aberrant interaction between VDAC1 and P-TAU in the brains of AD patients, which led to abnormalities in the structural and functional integrity of the mitochondria. The purpose of our study is to understand the protective effects of reduced VDAC1 against impaired mitochondrial dynamics and defective mitochondrial biogenesis in transgenic TAU mice. Recently, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with transgenic TAU mice to obtain double-mutant VDAC1+/−/TAU mice. Our goal was to evaluate whether a partial decrease in VDAC1 lessens the amount of mitochondrial toxicity in transgenic Tau (P301L) mice. We found that mitochondrial fission proteins were significantly reduced, and mitochondrial fusion and biogenesis proteins were increased in double-mutant mice compared to TAU mice. On the basis of these discoveries, the current work may have significance for the development of reduced-VDAC1-based treatments for individuals suffering from AD as well as other tauopathies. [ABSTRACT FROM AUTHOR]

Voltage-dependent anion channel-1 (VDAC1) is a highly regulated β-barrel membrane protein that mediates transport of ions and metabolites between the mitochondria and cytosol of the cell. VDAC1 co-purifies with cholesterol and is functionally regulated by cholesterol, among other endogenous lipids. Molecular modeling studies based on NMR observations have suggested five cholesterol-binding sites in VDAC1, but direct experimental evidence for these sites is lacking. Here, to determine the sites of cholesterol binding, we photolabeled purified mouse VDAC1 (mVDAC1) with photoactivatable cholesterol analogues and analyzed the photolabeled sites with both top-down mass spectrometry (MS), and bottom-up MS paired with a clickable, stable isotope-labeled tag, FLI-tag. Using cholesterol analogues with a diazirine in either the 7 position of the steroid ring (LKM38) or the aliphatic tail (KK174), we mapped a binding pocket in mVDAC1 localized to Thr83 and Glu73, respectively. When Glu73 was mutated to a glutamine, KK174 no longer photolabeled this residue, but instead labeled the nearby Tyr62 within this same binding pocket. The combination of analytical strategies employed in this work permits detailed molecular mapping of a cholesterol-binding site in a protein, including an orientation of the sterol within the site. Our work raises the interesting possibility that cholesterol-mediated regulation of VDAC1 may be facilitated through a specific binding site at the functionally important Glu73 residue.

Wuzi-Yanzong-Wan (WZYZW) is a classic prescription for male infertility. Our previous investigation has demonstrated that it can inhibit sperm apoptosis via affecting mitochondria, but the underlying mechanisms are unclear. The purpose of the present study was to explore the actions of WZYZW on mitochondrial permeability transition pore (mPTP) in mouse spermatocyte cell line (GC-2 cells) opened by atractyloside (ATR). At first, WZYZW-medicated serum was prepared from rats following oral administration of WZYZW for 7 days. GC-2 cells were divided into control group, model group, positive group, as well as 5%, 10%, 15% WZYZW-medicated serum group. Cyclosporine A (CsA) was used as a positive control. 50 μmol·L−1 ATR was added after drugs incubation. Cell viability was assessed using CCK-8. Apoptosis was detected using flow cytometry and TUNEL method. The opening of mPTP and mitochondrial membrane potential (MMP) were detected by Calcein AM and JC-1 fluorescent probe respectively. The mRNA and protein levels of voltage-dependent anion channel 1 (VDAC1), cyclophilin D (CypD), adenine nucleotide translocator (ANT), cytochrome C (Cyt C), caspase 3, 9 were detected by RT-PCR (real time quantity PCR) and Western blotting respectively. The results demonstrated that mPTP of GC-2 cells was opened after 24 hours of ATR treatment, resulting in decreased MMP and increased apoptosis. Pre-protection with WZYZ-medicated serum and CsA inhibited the opening of mPTP of GC-2 cells induced by ATR associated with increased MMP and decreased apoptosis. Moreover, the results of RT-qPCR and WB suggested that WZYZW-medicated serum could significantly reduce the mRNA and protein levels of VDAC1 and CypD, Caspase-3, 9 and CytC, as well as a increased ratio of Bcl/Bax. However, ANT was not significantly affected. Therefore, these findings indicated that WZYZW inhibited mitochondrial mediated apoptosis by attenuating the opening of mPTP in GC-2 cells. WZYZW-medicated serum inhibited the expressions of VDAC1 and CypD and increased the expression of Bcl-2, which affected the opening of mPTP and exerted protective and anti-apoptotic effects on GC-2 cell induced by ATR. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP)‐based chemotherapy is a preferred treatment for a broad spectrum of cancers, but the precise mechanisms of its hepatotoxicity are not yet clear. Recently, the role of voltage‐dependent anion channel protein 1 (VDAC1) in mitochondrial activity and cell apoptosis has attracted much attention. Our aim was to investigate the effects of mitochondrial outer membrane protein VDAC1 oligomerization in DDP‐induced hepatocyte apoptosis. L‐02 hepatocytes were divided into 4 groups: (a) control group, (b) 4,4'diisothiocyanate‐2,2'‐disulfonic acid (DIDS; 40 μm) group, (c) DDP (5 μm) group, and (d) DDP and DIDS combination group. Cell apoptosis was tested by Annexin V/FITC assay, protein expression of caspase‐3, γH2AX and NDUFB6 were observed by western blot assay, reactive oxygen species (ROS), and mitochondrial superoxide anion radical (O2•−) were detected by DCFH‐DA and MitoSOX probe, and DNA damage was assessed by comet assay. Moreover, the activity of mitochondrial respiratory chain complex I was determined by the colorimetry method. Compared with the control group, apoptosis rate and activated cleaved‐caspase‐3 protein, ROS and O2•− generation, DNA damage marker comet tail length, and γH2AX protein level increased in the DDP treatment group (P < 0.05). Activity of mitochondrial COXI decreased after DDP treatment (P < 0.05). DIDS, as a VDAC1 oligomerization inhibitor, antagonized DDP‐induced apoptosis by diminishing oxidative stress and DNA damage and protecting mitochondrial complex protein. These results show that VDAC1 oligomerization may play an important role in DDP‐induced hepatocyte apoptosis by increasing ROS and mtDNA leakage from VDAC1 pores, exacerbating oxidative stress and mtDNA damage. [ABSTRACT FROM AUTHOR]

The electrostatic properties of membrane proteins often reveal many of their key biophysical characteristics, such as ion channel selectivity and the stability of charged membrane-spanning segments. The Poisson-Boltzmann (PB) equation is the gold standard for calculating protein electrostatics, and the software APBSmem enables the solution of the PB equation in the presence of a membrane. Here, we describe significant advances to APBSmem, including full automation of system setup, per-residue energy decomposition, incorporation of PDB2PQR, calculation of membrane-induced pKa shifts, calculation of non-polar energies, and command-line scripting for large-scale calculations. We highlight these new features with calculations carried out on a number of membrane proteins, including the recently solved structure of the ion channel TRPV1 and a large survey of 1,614 membrane proteins of known structure. This survey provides a comprehensive list of residues with large electrostatic penalties for being embedded in the membrane, potentially revealing interesting functional information.

Ischemia/reperfusion (I/R) is a well‐known injury to the myocardium, but the mechanism involved remains elusive. In addition to the well‐accepted apoptosis theory, autophagy was recently found to be involved in the process, exerting a dual role as protection in ischemia and detriment in reperfusion. Activation of autophagy is mediated by mitochondrial permeability transition pore (MPTP) opening during reperfusion. In our previous study, we showed that MPTP opening is regulated by VDAC1, a channel protein located in the outer membrane of mitochondria. Thus, upregulation of VDAC1 expression is a possible trigger to cardiomyocyte autophagy via an unclear pathway. Here, we established an anoxia/reoxygenation (A/R) model in vitro to simulate the I/R process in vivo. At the end of A/R treatment, VDAC1, Beclin 1, and LC3‐II/I were upregulated, and autophagic vacuoles were increased in cardiomyocytes, which showed a connection of VDAC1 and autophagy development. These variations also led to ROS burst, mitochondrial dysfunction, and aggravated apoptosis. Knockdown of VDAC1 by RNAi could alleviate the above‐mentioned cellular damages. Additionally, the expression of PINK1 and Parkin was enhanced after A/R injury. Furthermore, Parkin was recruited to mitochondria from the cytosol, which suggested that the PINK1/Parkin autophagic pathway was activated during A/R. Nevertheless, the PINK1/Parkin pathway was effectively inhibited when VDAC1 was knocked‐down. Taken together, the A/R‐induced cardiomyocyte injury was mediated by VDAC1 upregulation, which led to cell autophagy via the PINK1/Parkin pathway, and finally aggravated apoptosis. [ABSTRACT FROM AUTHOR]

The voltage-dependent anion channel (VDAC) mediates the flow of metabolites and ions across the outer mitochondrial membrane of all eukaryotic cells. The open channel passes millions of ATP molecules per second, whereas the closed state exhibits no detectable ATP flux. High-resolution structures of VDAC1 revealed a 19-stranded β-barrel with an α-helix partially occupying the central pore. To understand ATP permeation through VDAC, we solved the crystal structure of mouse VDAC1 (mVDAC1) in the presence of ATP, revealing a low-affinity binding site. Guided by these coordinates, we initiated hundreds of molecular dynamics simulations to construct a Markov state model of ATP permeation. These simulations indicate that ATP flows through VDAC through multiple pathways, in agreement with our structural data and experimentally determined physiological rates.

Alzheimer’s disease (AD) is one of the most common forms of neurodegeneration, defined by reduced cognitive function, which is caused by the gradual death of neurons in the brain. Recent studies have shown an age-dependent rise in the levels of voltage-dependent anion channel 1 (VDAC1) in AD. In addition, we discovered an aberrant interaction between VDAC1 and P-TAU in the brains of AD patients, which led to abnormalities in the structural and functional integrity of the mitochondria. The purpose of our study is to understand the protective effects of reduced VDAC1 against impaired mitochondrial dynamics and defective mitochondrial biogenesis in transgenic TAU mice. Recently, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with transgenic TAU mice to obtain double-mutant VDAC1+/−/TAU mice. Our goal was to evaluate whether a partial decrease in VDAC1 lessens the amount of mitochondrial toxicity in transgenic Tau (P301L) mice. We found that mitochondrial fission proteins were significantly reduced, and mitochondrial fusion and biogenesis proteins were increased in double-mutant mice compared to TAU mice. On the basis of these discoveries, the current work may have significance for the development of reduced-VDAC1-based treatments for individuals suffering from AD as well as other tauopathies.

The present study aimed to explore how resveratrol (Res) confers myocardial protection by attenuating ferroptosis. In vivo and in vitro myocardial ischemia/reperfusion injury (MIRI) models were established, with or without Res pretreatment. The results showed that Res pretreatment effectively attenuated MIRI, as evidenced by increased cell viability, reduced lactate dehydrogenase activity, decreased infarct size, and maintained cardiac function. Moreover, Res pretreatment inhibited MIRI-induced ferroptosis, as shown by improved mitochondrial integrity, increased glutathione level, decreased prostaglandin-endoperoxide synthase 2 level, inhibited iron overload, and abnormal lipid peroxidation. Of note, Res pretreatment decreased or increased voltage-dependent anion channel 1/glutathione peroxidase 4 (VDAC1/GPX4) expression, which was increased or decreased via anoxia/reoxygenation (A/R) treatment, respectively. However, the overexpression of VDAC1 via pAd/VDAC1 and knockdown of GPX4 through Si-GPX4 reversed the protective effect of Res in A/R-induced H9c2 cells, whereas the inhibition of GPX4 with RSL3 abolished the protective effect of Res on mice treated with ischemia/reperfusion.Interestingly, knockdown of VDAC1 by Si-VDAC1 promoted the protective effect of Res on A/R-induced H9c2 cells and the regulation of GPX4. Finally, the direct interaction between VDAC1 and GPX4 was determined using co-immunoprecipitation. In conclusion, Res pretreatment could protect the myocardium against MIRI-induced ferroptosis via the VDAC1/GPX4 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in vascular smooth muscle cell (VSMC) phenotypic switching, which is an early pathogenic event in various vascular remodeling diseases (VRDs). However, the underlying mechanism is not fully understood., Methods: An IP‒LC‒MS/MS assay was conducted to identify new binding partners of G6PD involved in the regulation of VSMC phenotypic switching under platelet-derived growth factor-BB (PDGF-BB) stimulation. Co-IP, GST pull-down, and immunofluorescence colocalization were employed to clarify the interaction between G6PD and voltage-dependent anion-selective channel protein 1 (VDAC1). The molecular mechanisms involved were elucidated by examining the interaction between VDAC1 and apoptosis-related biomarkers, as well as the oligomerization state of VDAC1., Results: The G6PD level was significantly elevated and positively correlated with the synthetic characteristics of VSMCs induced by PDGF-BB. We identified VDAC1 as a novel G6PD-interacting molecule essential for apoptosis. Specifically, the G6PD-NTD region was found to predominantly contribute to this interaction. G6PD promotes VSMC survival and accelerates vascular neointimal hyperplasia by inhibiting VSMC apoptosis. Mechanistically, G6PD interacts with VDAC1 upon stimulation with PDGF-BB. By competing with Bax for VDAC1 binding, G6PD reduces VDAC1 oligomerization and counteracts VDAC1-Bax-mediated apoptosis, thereby accelerating neointimal hyperplasia., Conclusion: Our study showed that the G6PD-VDAC1-Bax axis is a vital switch in VSMC apoptosis and is essential for VSMC phenotypic switching and neointimal hyperplasia, providing mechanistic insight into early VRDs., (© 2024. The Author(s).)

MicroRNAs have been reported to be implicated in myocardial ischemia/reperfusion (I/R) injury. The purpose of this study was to investigate the effect of miR‐183‐5p on I/R injury. Overexpression of miR‐183‐5p by agomiR transfection alleviated cardiac dysfunction and significantly reduced the infarct size in rats with myocardial I/R. MiR‐183‐5p also alleviated myocardial apoptosis with reduced apoptotic cells and lower levels of apoptosis associated proteins. in vitro experiments were conducted on rat H9c2 cells treated with anoxia/reoxygenation (A/R). Annexin V/propidium iodide (PI) staining and flow cytometry reported that the ratio of apoptotic cells decreased by miR‐183‐5p transfection before A/R treatment. Moreover, according to binding sequence prediction and Dual luciferase reporter assay, we explored that voltage‐dependent anion channel 1 (VDAC1), which aggravates myocardial injury and apoptosis reported in our former research, was a target of miR‐183‐5p. In conclusion, miR‐183‐5p can efficiently attenuate I/R injury and miR‐183‐5p may exert its effect through repressing VDAC1 expression. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1(-/-) model of infantile NCL and Cln6(nclf) model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.

We previously reported that bakuchiol, a phenolic isoprenoid anticancer compound, and its analogs exert anti-influenza activity. However, the proteins targeted by bakuchiol remain unclear. Here, we investigated the chemical structures responsible for the anti-influenza activity of bakuchiol and found that all functional groups and C6 chirality of bakuchiol were required for its anti-influenza activity. Based on these results, we synthesized a molecular probe containing a biotin tag bound to the C1 position of bakuchiol. With this probe, we performed a pulldown assay for Madin-Darby canine kidney cell lysates and purified the specific bakuchiol-binding proteins with SDS-PAGE. Using nanoLC-MS/MS analysis, we identified prohibitin (PHB) 2, voltage-dependent anion channel (VDAC) 1, and VDAC2 as binding proteins of bakuchiol. We confirmed the binding of bakuchiol to PHB1, PHB2, and VDAC2 in vitro using Western blot analysis. Immunofluorescence analysis showed that bakuchiol was bound to PHBs and VDAC2 in cells and colocalized in the mitochondria. The knockdown of PHBs or VDAC2 by transfection with specific siRNAs, along with bakuchiol cotreatment, led to significantly reduced influenza nucleoprotein expression levels and viral titers in the conditioned medium of virus-infected Madin-Darby canine kidney cells, compared to the levels observed with transfection or treatment alone. These findings indicate that reducing PHBs or VDAC2 protein, combined with bakuchiol treatment, additively suppressed the growth of influenza virus. Our findings indicate that bakuchiol exerts anti-influenza activity via a novel mechanism involving these mitochondrial proteins, providing new insight for developing anti-influenza agents., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest regarding the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/introduction: This study investigated the roles of voltage-dependent anion channel 1-related differentially expressed genes (VRDEGs) in diabetic nephropathy (DN)., Materials and Methods: We downloaded two datasets from patients with DN, namely, GSE30122 and GSE30529, from the Gene Expression Omnibus database. VRDEGs associated with DN were obtained from the intersection of voltage-dependent anion channel 1-related genes from the GeneCards database, and differentially expressed genes were screened according to group (DN/healthy) in the two datasets. The enriched pathways of the VRDEGs were analyzed. Hub genes were selected using a protein-protein interaction network, and their predictive value was verified through receiver operating characteristic curve analysis. The CIBERSORTx software examined hub genes and immune cell infiltration associations. The protein expression of hub genes was verified through immunohistochemistry in 16-week-old db/db mice for experimentation as a model of type 2 DN. Finally, potential drugs targeting hub genes that inhibit DN development were identified., Results: A total of 57 VRDEGs were identified. The two datasets showed high expression of the PI3K, Notch, transforming growth factor-β, interleukin-10 and interleukin-17 pathways in DN. Five hub genes (ITGAM, B2M, LYZ, C3 and CASP1) associated with DN were identified and verified. Immunohistochemistry showed that the five hub genes were highly expressed in db/db mice, compared with db/m mice. The infiltration of immune cells was significantly correlated with the five hub genes., Conclusions: Five hub genes were significantly correlated with immune cell infiltration and might be crucial to DN development. This study provides insight into the mechanisms involved in the pathogenesis of DN., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Voltage-dependent anion channels (VDACs) are situated in the outer membrane of the mitochondria and serve as gatekeepers that control metabolite and ion exchange between the cytosol and mitochondria. VDAC1 is one of the most studied members of the VDAC protein family and is overexpressed in multiple types of cancer. However, the specific biological function and regulatory mechanism of VDAC1 in breast cancer remains unclear. The present study investigated the biological role of VDAC1 in breast cancer cells using an MTS assay. The association of clinicopathological features with VDAC1 in breast cancer was analyzed by Gene Expression Profiling Interactive Analysis. The regulatory mechanism of VDAC1 was determined by cell transfection, western blot analysis, reverse transcription-quantitative (q)PCR analysis, chromatin immunoprecipitation (ChIP) and ChIP-qPCR analysis. The results of the present study demonstrated that VDAC1 promoted breast cancer proliferation and was associated with a poor prognosis in patients with breast cancer. Additionally, it was observed that the expression of VDAC1 could be decreased by the bromodomain inhibitor (JQ1), and bromodomain-containing protein 4 (BRD4) was indicated to be a regulator of VDAC1. Furthermore, results suggested that VDAC1 may be involved in the resistance of breast cancer to JQ1. Collectively, the present findings uncovered important aspects of the function of VDAC1 in the tumor progression of breast cancer, and may provide a basis for potential therapeutic strategies for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Hyperglycemia in patients with diabetes induces vascular endothelial cell apoptosis and subsequent vasculopathy. The aim of the current study was to investigate the pathological mechanism of hyperglycemia-induced endothelial cell apoptosis and vasculopathy using human umbilical vein endothelial cells. As high glucose-induced apoptosis is caused by elevated mitochondrial permeability-mediated release of mitochondrial cytochrome c, the current study examined voltage-dependent anion channel (VDAC1), the controller of mitochondrial permeability, and its regulators, hexokinase2 (HK2), Bcl-2 and Bax. The current study demonstrated that HK2 may be involved in high glucose-induced cell apoptosis, as HK2 overexpression partially reversed high glucose-induced downregulation of mitochondrial/cellular HK2 and Bcl-2 as well as upregulation of mitochondrial Bax. These results suggest that HK2 overexpression partially reversed the reduced binding of HK2 and Bcl-2 and the enhanced binding of Bax to VDAC1, which reduced the high mitochondrial permeability observed under high-glucose conditions. Furthermore, high glucose reduced HK2 transcription via down-regulation of the HK2 transcriptional factor, peroxisome proliferator activated receptor γ (PPARγ). Taken together, these results suggest that PPARγ/HK2 may be novel targets for the prevention of diabetic vasculopathy. [ABSTRACT FROM AUTHOR]

Cardiac ischemia and reperfusion (IR) injury induces excessive emission of deleterious reactive O 2 and N 2 species (ROS/RNS), including the non-radical oxidant peroxynitrite (ONOO−) that can cause mitochondria dysfunction and cell death. In this study, we explored whether IR injury in isolated hearts induces tyrosine nitration of adenine nucleotide translocase (ANT) and alters its interaction with the voltage-dependent anion channel 1 (VDAC1). We found that IR injury induced tyrosine nitration of ANT and that exposure of isolated cardiac mitochondria to ONOO− induced ANT tyrosine, Y81, nitration. The exposure of isolated cardiac mitochondria to ONOO− also led ANT to form high molecular weight proteins and dissociation of ANT from VDAC1. We found that IR injury in isolated hearts, hypoxic injury in H9c2 cells, and ONOO− treatment of H9c2 cells and isolated mitochondria, each decreased mitochondrial bound-hexokinase II (HK II), which suggests that ONOO− caused HK II to dissociate from mitochondria. Moreover, we found that mitochondria exposed to ONOO− induced VDAC1 oligomerization which may decrease its binding with HK II. We have reported that ONOO− produced during cardiac IR injury induced tyrosine nitration of VDAC1, which resulted in conformational changes of the protein and increased channel conductance associated with compromised cardiac function on reperfusion. Thus, our results imply that ONOO− produced during IR injury and hypoxic stress impeded HK II association with VDAC1. ONOO− exposure nitrated mitochondrial proteins and also led to cytochrome c (cyt c) release from mitochondria. In addition, in isolated mitochondria exposed to ONOO− or obtained after IR, there was significant compromise in mitochondrial respiration and delayed repolarization of membrane potential during oxidative (ADP) phosphorylation. Taken together, ONOO− produced during cardiac IR injury can nitrate tyrosine residues of two key mitochondrial membrane proteins involved in bioenergetics and energy transfer to contribute to mitochondrial and cellular dysfunction. • Peroxynitrite (ONOO−) induces tyrosine nitration of ANT and VDAC1. • ONOO− cause dissociation of ANT from VDAC1, and HK II from VDAC1 • Protein dissociation enhances cytochrome c release from mitochondria. • ONOO− impairs mitochondrial bioenergetics, and compromises cardiac function after IR. [ABSTRACT FROM AUTHOR]

Abstract Our previous studies showed that the effect of resveratrol preventing mitochondrial permeability transition pore (mPTP) opening in myocardial ischemia/reperfusion injury was achieved by regulating voltage-dependent anion channel 1 (VDAC1). However, the underlying mechanism remains unclear. Previous studies demonstrated that the activity and function of VDAC1 are highly regulated by post-translational modification. In present study, we investigated whether resveratrol modulates VDAC1 phosphorylation to achieve cardioprotection and explored the signaling pathways involved. Our findings demonstrated that anoxia/reoxygenation (A/R) treatment, an ischemia/reperfusion model in vitro, enhanced VDAC1 phosphorylation in cardiomyocytes. Moreover, we found phosphorylated VDAC1 showed increased affinity to Bax, whereas interaction with hexokinase 2 (HK2) was reduced. Accordingly, the generation of reactive oxygen species increased, the mitochondrial membrane potential collapsed, mPTP opening increased and cytochrome c released into cytoplasm, thereby leading to increased apoptosis. Moreover, our data showed that pretreatment with resveratrol prior to A/R injury inhibited VDAC1 phosphorylation. Dephosphorylated VDAC1 using pretreated resveratrol promoted dissociation with Bax and binding to HK2, which subsequently protected cardiomyocytes against A/R injury. In addition, Akt and its downstream glycogen synthase kinase 3 β (GSK3β) were phosphorylated by the action of resveratrol. Akt inhibitor IV abrogated Akt-GSK3β phosphorylation and thereby abolished the dephosphorylation activity of resveratrol on VDAC1. Moreover, all resveratrol-mediated protective effects on A/R injured cardiomyocytes were abolished by Akt inhibitor IV. Taken together, our data indicated that A/R injury enhanced VDAC1 phosphorylation in cardiomyocytes, whereas pretreatment with resveratrol dephosphorylated VDAC1 through the Akt-GSK3β pathway, thereby protecting cardiomyocytes against A/R injury. [ABSTRACT FROM AUTHOR]

Study Objectives: This study verified that sleep deprivation before and after skin/muscle incision and retraction (SMIR) surgery increased the risk of chronic pain and investigated the underlying roles of microglial voltage-dependent anion channel 1 (VDAC1) signaling., Methods: Adult mice received 6 hours of total sleep deprivation from 1 day prior to SMIR until the third day after surgery. Mechanical and heat-evoked pain was assessed before and within 21 days after surgery. Microglial activation and changes in VDAC1 expression and oligomerization were measured. Minocycline was injected to observe the effects of inhibiting microglial activation on pain maintenance. The VDAC1 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and oligomerization inhibitor VBIT-4 were used to determine the roles of VDAC1 signaling on microglial adenosine 5' triphosphate (ATP) release, inflammation (IL-1β and CCL2), and chronicity of pain., Results: Sleep deprivation significantly increased the pain duration after SMIR surgery, activated microglia, and enhanced VDAC1 signaling in the spinal cord. Minocycline inhibited microglial activation and alleviated sleep deprivation-induced pain maintenance. Lipopolysaccharide (LPS)-induced microglial activation was accompanied by increased VDAC1 expression and oligomerization, and more VDAC1 was observed on the cell membrane surface compared with control. DIDS and VBIT-4 rescued LPS-induced microglial ATP release and IL-1β and CCL2 expression. DIDS and VBIT-4 reversed sleep loss-induced microglial activation and pain chronicity in mice, similar to the effects of minocycline. No synergistic effects were found for minocycline plus VBIT-4 or DIDS., Conclusions: Perioperative sleep deprivation activated spinal microglia and increases the risk of chronic postsurgical pain in mice. VDAC1 signaling regulates microglial activation-related ATP release, inflammation, and chronicity of pain., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate the molecular mechanism of hyperglycemia-induced apoptosis of vascular endothelial cells.Methods: HUVEC cells were used to mimic the pathological status of endothelial cells in the condition of hyperglycemia. The cell viability was detected by MTT assay, the mitochondrial membrane potential was detected with JC-1 staining and flow cytometry assay,the transcription levels of hexokinaseⅡ(HKⅡ) were detected using reverse transcription-polymerase PCR and luciferase assay. Western blot and immune co-precipitation were used to analyse the expression of VDAC1, HK Ⅱ, Bcl-2 and Bax on the mitochondrial outer membrane and their interactions. Results: The viability of HUVEC cells incubated in medium containing 25 or 100 m M glucose was reduced by 19.21 %±4.13 % and 25.29 %±5.78 % respectively; mitochondrial membrane potential was reduced by 34.19 % ±5.13 %and 58.63 % ±4.78 % respectively; HK Ⅱ protein expression levels were reduced by 13.97 % ±6.32 % and 35.13 % ±5.18 %respectively; the interactions between HKⅡ and VDAC1 were both reduced in the two groups, while the Bax and VDAC1 interactions were compensatorily enhanced. Conclusion: High glucose reduced the HK Ⅱ expression, increased mitochondrial permeability and eventually induced the apoptosis of HUVEC cells. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Although an accumulation of brain amyloid-β (Aβ) peptide and hyperphosphorylated tau protein have been implicated in the pathogenesis of AD, the etiology of the disease remains unclear. Mitochondrial dysfunction has been identified as an early event in AD pathogenesis and is reflected by reduced metabolism, disruption of Ca 2+ homeostasis, and increased levels of reactive oxygen species, lipid peroxidation, and apoptosis. The focus of this review is the involvement of mitochondrial dysfunction in AD, and specifically, the role of the voltage-dependent anion channel 1 (VDAC1), which has been linked to AD pathogenesis. VDAC1 is a multi-functional protein, expressed in the mitochondria and other cell compartments, including the plasma membrane. The protein regulates the main metabolic and energetic functions of the cell, including Ca 2+ homeostasis, oxidative stress, and mitochondria-mediated apoptosis. VDAC1 represents a hub protein that interacts with over 150 other proteins including phosphorylated tau, Aβ, and γ-secretase, and participates in their toxicity. The high levels of VDAC1 demonstrated post-mortem in the brains of AD patients and in amyloid precursor protein (APP) transgenic mice prompted the hypothesis that the protein may be associated with neuronal cell destruction since over-expression of VDAC1 triggers cell death. Thus, targeting mitochondrial dysfunction via VDAC1, to prevent this pro-apoptotic activity, could represent a novel strategy for inhibiting cell death. In addition, the review also discusses possible VDAC1 involvement in the link between AD and diabetes and the inverse association between cancer and AD. [ABSTRACT FROM AUTHOR]

Mitochondrial membrane permeability is closely related to cerebral ischemia/reperfusion (I/R) injury. This paper explored the neuroprotective effect of picroside II (Picr), which inhibits the permeability of mitochondrial permeability transition pore (mPTP) and endonuclease G (EndoG) release from mitochondria into cytoplasm after cerebral I/R in rats. After 2 h of cerebral ischemia and 24 h of reperfusion in rats with different intervention measures, the neurobehavioral function, infarction volume, and reactive oxygen species (ROS) content in brain tissues were observed by modified neurological severity scale (mNSS), triphenyl tetrazolium chloride (TTC) staining, and enzyme-linked immunosorbent assay, respectively. The permeability of mPTP was assayed using spectrophotometry. The morphology and apoptotic cells of brain tissues were observed by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay, respectively. The expressions of EndoG and voltage-dependent anion channel 1 (VDAC1) were determined by immunohistochemical assay and western blot. The Picr group exhibited clear decreases in mNSS scores, ROS content, number of apoptotic cells, mPTP permeability and expression of VDAC1, and EndoG in cytoplasm and nuclei, and the morphology of brain tissue was improved as compared with the model group ( P < 0.05). Picr could attenuate cerebral I/R injury by downregulating the expression of VDAC1 and decreasing the permeability of mPTP, thereby inhibiting EndoG release from mitochondria into cytoplasm. [ABSTRACT FROM AUTHOR]

Voltage-dependent anion channel 1 (VDAC1) is thought to contribute to the progression of tumor development. However, whether VDAC1 contributes to bone cancer pain remains unknown. In this study, we found that the expression of VDAC1 was upregulated in the L2-5 segments of the spinal dorsal horn at 2 and 3 weeks after injection of tumor cells into the tibial cavity. Intrathecal injection of a VDAC1 inhibitor significantly reversed the pain hypersensitivity and reduced the over-expression of Toll-like receptor 4 (TLR4). Intrathecal injection of minocycline, an inhibitor of microglia, also attenuated the pain hypersensitivity of rat models of bone cancer pain. These results suggest that VDAC1 plays a significant role in the development of complicated cancer pain, possibly by regulating the expression of TLR4. [ABSTRACT FROM AUTHOR]

Cancer cells share several properties, high proliferation potential, reprogramed metabolism, and resistance to apoptotic cues. Acquiring these hallmarks involves changes in key oncogenes and non-oncogenes essential for cancer cell survival and prosperity, and is accompanied by the increased energy requirements of proliferating cells. Mitochondria occupy a central position in cell life and death with mitochondrial bioenergetics, biosynthesis, and signaling are critical for tumorigenesis. Voltage-dependent anion channel 1 (VDAC1) is situated in the outer mitochondrial membrane (OMM) and serving as a mitochondrial gatekeeper. VDAC1 allowing the transfer of metabolites, fatty acid ions, Ca2+, reactive oxygen species, and cholesterol across the OMM and is a key player in mitochondrial-mediate apoptosis. Moreover, VDAC1 serves as a hub protein, interacting with diverse sets of proteins from the cytosol, endoplasmic reticulum, and mitochondria that together regulate metabolic and signaling pathways. The observation that VDAC1 is over-expressed in many cancers suggests that the protein may play a pivotal role in cancer cell survival. However, VDAC1 is also important in mitochondria-mediated apoptosis, mediating release of apoptotic proteins and interacting with anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-xL, and hexokinase (HK), which are also highly expressed in many cancers. Strategically located in a “bottleneck” position, controlling metabolic homeostasis and apoptosis, VDAC1 thus represents an emerging target for anti-cancer drugs. This review presents an overview on the multi-functional mitochondrial protein VDAC1 performing several functions and interacting with distinct sets of partners to regulate both cell life and death, and highlights the importance of the protein for cancer cell survival. We address recent results related to the mechanisms of VDAC1-mediated apoptosis and the potential of associated proteins to modulate of VDAC1 activity, with the aim of developing VDAC1-based approaches. The first strategy involves modification of cell metabolism using VDAC1-specific small interfering RNA leading to inhibition of cancer cell and tumor growth and reversed oncogenic properties. The second strategy involves activation of cancer cell death using VDAC1-based peptides that prevent cell death induction by anti-apoptotic proteins. Finally, we discuss the potential therapeutic benefits of treatments and drugs leading to enhanced VDAC1 expression or targeting VDAC1 to induce apoptosis.