scholarly journals VDAC1 in the diseased myocardium and the effect of VDAC1-interacting compound on atrial fibrosis induced by hyperaldosteronism

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hadar Klapper-Goldstein ◽  
Ankit Verma ◽  
Sigal Elyagon ◽  
Roni Gillis ◽  
Michael Murninkas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Immunohistochemical Analysis ◽  
Voltage Dependent Anion Channel ◽  
Cardiac Tissues ◽  
Therapeutic Implications ◽  
Voltage Dependent ◽  
Models Of Lupus

AbstractThe voltage-dependent anion channel 1 (VDAC1) is a key player in mitochondrial function. VDAC1 serves as a gatekeeper mediating the fluxes of ions, nucleotides, and other metabolites across the outer mitochondrial membrane, as well as the release of apoptogenic proteins initiating apoptotic cell death. VBIT-4, a VDAC1 oligomerization inhibitor, was recently shown to prevent mitochondrial dysfunction and apoptosis, as validated in mouse models of lupus and type-2 diabetes. In the present study, we explored the expression of VDAC1 in the diseased myocardium of humans and rats. In addition, we evaluated the effect of VBIT-4 treatment on the atrial structural and electrical remodeling of rats exposed to excessive aldosterone levels. Immunohistochemical analysis of commercially available human cardiac tissues revealed marked overexpression of VDAC1 in post-myocardial infarction patients, as well as in patients with chronic ventricular dilatation\dysfunction. In agreement, rats exposed to myocardial infarction or to excessive aldosterone had a marked increase of VDAC1 in both ventricular and atrial tissues. Immunofluorescence staining indicated a punctuated appearance typical for mitochondrial-localized VDAC1. Finally, VBIT-4 treatment attenuated the atrial fibrotic load of rats exposed to excessive aldosterone without a notable effect on the susceptibility to atrial fibrillation episodes induced by burst pacing. Our results indicate that VDAC1 overexpression is associated with myocardial abnormalities in common pathological settings. Our data also indicate that inhibition of the VDAC1 can reduce excessive fibrosis in the atrial myocardium, a finding which may have important therapeutic implications. The exact mechanism\s of this beneficial effect need further studies.

scholarly journals MAVS Regulates Apoptotic Cell Death by Decreasing K48-Linked Ubiquitination of Voltage-Dependent Anion Channel 1

2013 ◽  
Vol 33 (16) ◽  
pp. 3137-3149 ◽  
Author(s):  
Kai Guan ◽  
Zirui Zheng ◽  
Ting Song ◽  
Xiang He ◽  
Changzhi Xu ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Apoptotic Cell Death ◽  
Type I ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Consequent Reduction ◽  
Mitochondrial Antiviral Signaling ◽  
Induced Apoptosis

The mitochondrial antiviral signaling protein MAVS (IPS-1, VISA, or Cardif) plays an important role in the host defense against viral infection by inducing type I interferon. Recent reports have shown that MAVS is also critical for virus-induced apoptosis. However, the mechanism of MAVS-mediated apoptosis induction remains unclear. Here, we show that MAVS binds to voltage-dependent anion channel 1 (VDAC1) and induces apoptosis by caspase-3 activation, which is independent of its role in innate immunity. MAVS modulates VDAC1 protein stability by decreasing its degradative K48-linked ubiquitination. In addition, MAVS knockout mouse embryonic fibroblasts (MEFs) display reduced VDAC1 expression with a consequent reduction of the vesicular stomatitis virus (VSV)-induced apoptosis response. Notably, the upregulation of VDAC1 triggered by VSV infection is completely abolished in MAVS knockout MEFs. We thus identify VDAC1 as a target of MAVS and describe a novel mechanism of MAVS control of virus-induced apoptotic cell death.

scholarly journals In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death

2004 ◽  
Vol 377 (2) ◽  
pp. 347-355 ◽  
Author(s):  
Heftsi AZOULAY-ZOHAR ◽  
Adrian ISRAELSON ◽  
Salah ABU-HAMAD ◽  
Varda SHOSHAN-BARMATZ
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Direct Interaction ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Metabolic Intermediate ◽  
Voltage Dependent

In tumour cells, elevated levels of mitochondria-bound isoforms of hexokinase (HK-I and HK-II) result in the evasion of apoptosis, thereby allowing the cells to continue proliferating. The molecular mechanisms by which bound HK promotes cell survival are not yet fully understood. Our studies relying on the purified mitochondrial outer membrane protein VDAC (voltage-dependent anion channel), isolated mitochondria or cells in culture suggested that the anti-apoptotic activity of HK-I occurs via modulation of the mitochondrial phase of apoptosis. In the present paper, a direct interaction of HK-I with bilayer-reconstituted purified VDAC, inducing channel closure, is demonstrated for the first time. Moreover, HK-I prevented the Ca2+-dependent opening of the mitochondrial PTP (permeability transition pore) and release of the pro-apoptotic protein cytochrome c. The effects of HK-I on VDAC activity and PTP opening were prevented by the HK reaction product glucose 6-phosphate, a metabolic intermediate in most biosynthetic pathways. Furthermore, glucose 6-phosphate re-opened both the VDAC and the PTP closed by HK-I. The HK-I-mediated effects on VDAC and PTP were not observed using either yeast HK or HK-I lacking the N-terminal hydrophobic peptide responsible for binding to mitochondria, or in the presence of an antibody specific for the N-terminus of HK-I. Finally, HK-I overexpression in leukaemia-derived U-937 or vascular smooth muscle cells protected against staurosporine-induced apoptosis, with a decrease of up to 70% in cell death. These results offer insight into the mechanisms by which bound HK promotes tumour cell survival, and suggests that its overexpression not only ensures supplies of energy and phosphometabolites, but also reflects an anti-apoptotic defence mechanism.

scholarly journals The voltage-dependent anion channel-1 modulates apoptotic cell death

2005 ◽  
Vol 12 (7) ◽  
pp. 751-760 ◽  
Author(s):  
H Zaid ◽  
S Abu-Hamad ◽  
A Israelson ◽  
I Nathan ◽  
V Shoshan-Barmatz
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Apoptotic Cell Death ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

scholarly journals VDAC1 and the TSPO: Expression, Interactions, and Associated Functions in Health and Disease States

2019 ◽  
Vol 20 (13) ◽  
pp. 3348 ◽  
Author(s):  
Varda Shoshan-Barmatz ◽  
Srinivas Pittala ◽  
Dario Mizrachi
Keyword(s):  
Apoptotic Cell ◽  
Anion Channel ◽  
Translocator Protein ◽  
Voltage Dependent Anion Channel ◽  
Disease States ◽  
Voltage Dependent ◽  
Associated Functions ◽  
Health And Disease ◽  
Potential Basis ◽  
Tspo Expression

The translocator protein (TSPO), located at the outer mitochondrial membrane (OMM), serves multiple functions and contributes to numerous processes, including cholesterol import, mitochondrial metabolism, apoptosis, cell proliferation, Ca2+ signaling, oxidative stress, and inflammation. TSPO forms a complex with the voltage-dependent anion channel (VDAC), a protein that mediates the flux of ions, including Ca2+, nucleotides, and metabolites across the OMM, controls metabolism and apoptosis and interacts with many proteins. This review focuses on the two OMM proteins TSPO and VDAC1, addressing their structural interaction and associated functions. TSPO appears to be involved in the generation of reactive oxygen species, proposed to represent the link between TSPO activation and VDAC, thus playing a role in apoptotic cell death. In addition, expression of the two proteins in healthy brains and diseased states is considered, as is the relationship between TSPO and VDAC1 expression. Both proteins are over-expressed in in brains from Alzheimer’s disease patients. Finally, TSPO expression levels were proposed as a biomarker of some neuropathological settings, while TSPO-interacting ligands have been considered as a potential basis for drug development.

scholarly journals Voltage-dependent anion channels mediated apoptosis in refractory epilepsy

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 745-753
Author(s):  
Yan Zhao ◽  
Wen-Jing Jiang ◽  
Lin Ma ◽  
Yan Lin ◽  
Xing-Bang Wang
Keyword(s):  
Cell Death ◽  
Essential Role ◽  
Refractory Epilepsy ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Anion Channels ◽  
Voltage Dependent Anion Channel ◽  
Caspase 9 ◽  
Voltage Dependent

AbstractThe purpose of this study was to investigate the role of voltage-dependent anion channel (VDAC) in mitochondria-mediated apoptosis of neurons in refractory epilepsy. Western blot analyses were carried out to detect the changes in cytochrome C, caspase 9, Bax, and Bcl-2. TUNEL assays were also carried out to investigate cell apoptosis under the upregulation and downregulation of VDAC1 with or without Bax or Bcl-2. VDAC1 induced Bax, Bcl-2, and caspase 9, increasing the release of cytochrome C. VDAC1 played an essential role in the apoptotic cell death of refractory epilepsy. It is concluded that VDAC1 plays an important role in refractory epilepsy and could be a possible therapeutic target of anti-epileptic drugs. The current study provides a new understanding of the possible mechanisms of refractory epilepsy.

VDAC1 cysteine residues: topology and function in channel activity and apoptosis

2010 ◽  
Vol 427 (3) ◽  
pp. 445-454 ◽  
Author(s):  
Lior Aram ◽  
Shay Geula ◽  
Nir Arbel ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Apoptotic Cell ◽  
Anion Channel ◽  
Cross Linking ◽  
Cysteine Residues ◽  
Channel Activity ◽  
Voltage Dependent Anion Channel ◽  
Oxidation Reduction ◽  
Voltage Dependent ◽  
And Function ◽  
Interfering Rna

The VDAC (voltage-dependent anion channel) is proposed to control metabolic cross-talk between mitochondria and the cytosol, as well as apoptotic cell death. It has been suggested that apoptosis is modulated by the oxidation state of VDAC. Since cysteine residues are the major target for oxidation/reduction, we verified whether one or both VDAC1 cysteine residues are involved in VDAC1-mediated transport or apoptosis activities. To assess the function of VDAC1 cysteine residues in channel activity and to probe cysteine topology with respect to facing the pore or the bilayer, we used thiol-modifying agents, namely membrane-permeable NEM (N-ethylmaleimide), bulky charged 5-FM (fluorescein-5-maleimide) and the cross-linking reagent BMOE [bis(maleimido)ethane]. Bilayer-reconstituted VDAC conductance was decreased by 5-FM, but not by NEM, whereas 5-FM had no effect on NEM-labelled VDAC conductance. BMOE caused the formation of dimeric VDAC1, suggesting that one of the two VDAC1 cysteine residues is exposed and available for cross-linking. The results thus suggest that one of the VDAC1 cysteine residues faces the VDAC pore, whereas the second is oriented towards the lipid bilayer. Mutated rat VDAC1 in which the two cysteine residues, Cys127 and Cys232, were replaced by alanine residues showed channel activity like native VDAC1 and, when expressed in cells, was localized to mitochondria. Human VDAC1-shRNA (small hairpin RNA)- or -siRNA (small interfering RNA)-treated cells, expressing low levels of endogenous human VDAC1 together with native or cysteine-less rat VDAC1, undergo apoptosis as induced by overexpression of these VDAC1 or upon treatment with reactive oxygen species-producing agents, H2O2, As2O3 or selenite, suggesting that the two cysteine residues are not required for apoptosis or VDAC1 oligomerization.

scholarly journals Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1

2008 ◽  
Vol 283 (19) ◽  
pp. 13482-13490 ◽  
Author(s):  
Salah Abu-Hamad ◽  
Hilal Zaid ◽  
Adrian Israelson ◽  
Edna Nahon ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Apoptotic Cell Death ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

Coupling of ryanodine receptor 2 and voltage-dependent anion channel 2 is essential for Ca2+ transfer from the sarcoplasmic reticulum to the mitochondria in the heart

2012 ◽  
Vol 447 (3) ◽  
pp. 371-379 ◽  
Author(s):  
Choon Kee Min ◽  
Dong Rim Yeom ◽  
Kyung-Eun Lee ◽  
Hye-Kyeong Kwon ◽  
Moonkyung Kang ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Glutathione Transferase ◽  
Anion Channel ◽  
Functional Coupling ◽  
Molecular Architecture ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Mitochondrial Junctions

The structural proximity and functional coupling between the SR (sarcoplasmic reticulum) and mitochondria have been suggested to occur in the heart. However, the molecular architecture involved in the SR–mitochondrial coupling remains unclear. In the present study, we performed various genetic and Ca2+-probing studies to resolve the proteins involved in the coupling process. By using the bacterial 2-hybrid, glutathione transferase pull-down, co-immunoprecipitation and immunocytochemistry assays, we found that RyR2 (ryanodine receptor type 2), which is physically associated with VDAC2 (voltage-dependent anion channel 2), was co-localized in SR–mitochondrial junctions. Furthermore, a fractionation study revealed that VDAC2 was co-localized with RyR2 only in the subsarcolemmal region. VDAC2 knockdown by targeted short hairpin RNA led to an increased diastolic [Ca2+] (calcium concentration) and abolishment of mitochondrial Ca2+ uptake. Collectively, the present study suggests that the coupling of VDAC2 with RyR2 is essential for Ca2+ transfer from the SR to mitochondria in the heart.

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