更新于：2024-09-19

VDAC2

更新于：2024-09-19

基本信息

别名

hVDAC2、Outer mitochondrial membrane protein porin 2、VDAC-2

+ [3]

简介

Forms a channel through the mitochondrial outer membrane that allows diffusion of small hydrophilic molecules (By similarity). The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV (By similarity). The open state has a weak anion selectivity whereas the closed state is cation-selective (By similarity). Binds various lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterol cholesterol (PubMed:31015432). Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway (PubMed:31015432).

关联

项与 VDAC2 相关的药物

Erastin

爱拉斯汀

靶点

SLC7A11 x VDAC1 x VDAC2 x VDAC3 x p53

作用机制

SLC7A11 modulators [+4]

在研机构

Prolexys Pharmaceuticals, Inc. [+1]

原研机构-

在研适应症

突变相关肿瘤 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

WEHI-9625

靶点

VDAC2

作用机制

VDAC2 agonists

在研机构

The Walter & Eliza Hall Institute of Medical Research

原研机构

The Walter & Eliza Hall Institute of Medical Research

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 VDAC2 相关的临床结果

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100 项与 VDAC2 相关的转化医学

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0 项与 VDAC2 相关的专利（医药）

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348

项与 VDAC2 相关的文献（医药）

2024-10-01·Ecotoxicology and Environmental Safety

Lysosomal iron accumulation and subsequent lysosomes-mitochondria iron transmission mediate PFOS-induced hepatocyte ferroptosis

Article

作者: Qiu, Tianming ; Liang, Peiyao ; Sun, Xiance ; Yao, Xiaofeng ; Yang, Guang ; Zhang, Jingyuan ; Li, Qiujuan ; Feng, Ruzhen ; Li, Jixun ; Yang, Wei

Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5-24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.

2024-09-01·Biological Trace Element Research

p53-Mediated Mitochondrial Translocation of EI24 Triggered by ER Stress Plays an Important Role in Arsenic-Induced Liver Damage via Activating Mitochondrial Apoptotic Pathway

Article

作者: Liu, Chunyan ; Zhang, Aihua

Chronic arsenic poisoning is a public health problem worldwide. In addition to skin lesions, the detrimental effect of arsenic poisoning on liver damage is one of the major issues. Our previous studies demonstrated that endoplasmic reticulum (ER) stress and p53 were associated with arsenic-induced liver damage. Literature has shown that EI24 is involved in hepatocyte hypertrophy; however, the underlying role and mechanism in arsenic-induced liver damage have not been fully elucidated. In this study, we explored the role of ER stress, p53, and EI24 as well as the regulatory relationship in arsenic poisoning populations and L-02 cells treated with distinct concentration NaAsO₂ (2.5, 5, 10, and 20 μM). Results showed that as with arsenic dose increment, expression levels of ER stress key proteins GRP78, ATF4, and CHOP were significantly enhanced. Additionally, p53 expression in nucleus, p53 phosphorylation at Ser15 and Ser1392, and p53 acetylation at lys382 were significantly increased in NaAsO₂-treated L-02 cells. ER stress inhibitor 4-phenylbutyric acid (4-PBA) decreased the expression of p53 phosphorylation at Ser 392, p53 acetylation at lys382, and p53 expression in nucleus. Additionally, in 5 μM NaAsO₂ condition, p53 inhibitor pifithrin-α (PFT-α) aggravated 5 μM NaAsO₂-induced GRP78, ATF4, and CHOP expressions, cell apoptosis, and protein-SH consumption. But in 20 μM NaAsO₂ condition, PFT-α attenuated NaAsO₂-induced cell apoptosis. Further results showed that 20 μM NaAsO₂ facilitated translocation of EI24 from ER to mitochondrion and interaction with VDAC2, leading to activate mitochondrial apoptotic pathway, but not observed in the 5-μM NaAsO₂ group. Moreover, PFT-α and 4-PBA inhibited 20 μM NaAsO₂-induced EI24 expression in mitochondrion. Collectively, our results indicated that arsenic induced p53 activation via ER stress, under relatively low NaAsO₂ concentration, NaAsO₂-triggered p53 activation protected cells from apoptosis by alleviating ER stress. Another finding was that under relatively high NaAsO₂ concentration, NaAsO₂-activated p53 facilitated EI24 mitochondrial translocation and caused mitochondrial permeability increase, which represented a switch of p53 from a benefit role to pro-apoptosis function in NaAsO₂-treated cells. The study contributed to in-depth understanding the mechanism of arsenic-induced liver damage and providing potential clues for following study.

2024-08-16·ACS Chemical Biology

Dual-Probe Activity-Based Protein Profiling Reveals Site-Specific Differences in Protein Binding of EGFR-Directed Drugs

Article

作者: Pohl, Elena E ; Baggelaar, Marc P ; van Bergen, Wouter ; Fiala, Jan ; Žuna, Kristina ; Heck, Albert J R

Comparative, dose-dependent analysis of interactions between small molecule drugs and their targets, as well as off-target interactions, in complex proteomes is crucial for selecting optimal drug candidates. The affinity of small molecules for targeted proteins is largely dictated by interactions between amino acid side chains and these drugs. Thus, studying drug-protein interactions at an amino acid resolution provides a comprehensive understanding of the drug selectivity and efficacy. In this study, we further refined the site-specific activity-based protein profiling strategy (ABPP), PhosID-ABPP, on a timsTOF HT mass spectrometer. This refinement enables dual dose-dependent competition of inhibitors within a single cellular proteome. Here, a comparative analysis of two activity-based probes (ABPs), developed to selectively target the epidermal growth factor receptor (EGFR), namely, PF-06672131 (PF131) and PF-6422899 (PF899), facilitated the simultaneous identification of ABP-specific binding sites at a proteome-wide scale within a cellular proteome. Dose-dependent probe-binding preferences for proteinaceous cysteines, even at low nanomolar ABP concentrations, could be revealed. Notably, in addition to the intrinsic affinity of the electrophilic probes for specific sites in targeted proteins, the observed labeling intensity is influenced by several other factors. These include the efficiency of cellular uptake, the stability of the probes, and their intracellular distribution. While both ABPs showed comparable labeling efficiency for EGFR, PF131 had a broader off-target reactivity profile. In contrast, PF899 exhibited a higher labeling efficiency for the ERBB2 receptor and bound to catalytic cysteines in several other enzymes, which is likely to disrupt their catalytic activity. Notably, PF131 effectively labeled ADP/ATP translocase proteins at a concentration of just 1 nm, and we found this affected ATP transport. Analysis of the effect of PF131 and its parent inhibitor Afatinib on murine translocase SLC25A4 (ANT1)-mediated ATP transport strongly indicated that PF131 (10 μM) partially blocked ATP transport. Afatinib was less efficient at inhibiting ATP transport by SLC25A4 than PF131, and the reduction of ATP transport by Afatinib was not significant. Follow-up analysis is required to evaluate the affinity of these inhibitors for ADP/ATP translocase SLC25A4 in more detail. Additionally, the analysis of different binding sites within the EGF receptor and the voltage-dependent anion channel 2 revealed secondary binding sites of both probes and provided insights into the binding poses of inhibitors on these proteins. Insights from the PhosID-ABPP analysis of these two ABPs serve as a valuable resource for understanding drug on- and off-target engagement in a dose- and site-specific manner.