scholarly journals Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

2015 ◽  
Vol 35 (9) ◽  
pp. 1491-1505 ◽  
Author(s):  
M. Christiane Brahimi-Horn ◽  
Sandra Lacas-Gervais ◽  
Ricardo Adaixo ◽  
Karine Ilc ◽  
Matthieu Rouleau ◽  
...  
Keyword(s):  
Cell Survival ◽  
Hypoxia Inducible Factor ◽  
Anion Channel ◽  
Metabolic Reprogramming ◽  
Hypoxic Cell ◽  
Voltage Dependent Anion Channel ◽  
Drug Induced ◽  
Hypoxia Inducible Factor 1 ◽  
Voltage Dependent ◽  
Induced Apoptosis

The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53.

scholarly journals Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

2015 ◽  
Vol 112 (41) ◽  
pp. E5590-E5599 ◽  
Author(s):  
Shamim Naghdi ◽  
Péter Várnai ◽  
György Hajnóczky
Keyword(s):  
Sequence Similarity ◽  
Anion Channel ◽  
Loss Of Function ◽  
Voltage Dependent Anion Channel ◽  
Fundamental Function ◽  
Cytoplasmic Surface ◽  
Voltage Dependent ◽  
Critical Residues ◽  
Induced Apoptosis ◽  
Relevant Domain

Voltage-dependent anion channel (VDAC) proteins are major components of the outer mitochondrial membrane. VDAC has three isoforms with >70% sequence similarity and redundant roles in metabolite and ion transport. However, only Vdac2−/− (V2−/−) mice are embryonic lethal, indicating a unique and fundamental function of VDAC2 (V2). Recently, a specific V2 requirement was demonstrated for mitochondrial Bak import and truncated Bid (tBid)-induced apoptosis. To determine the relevant domain(s) of V2 involved, VDAC1 (V1) and V2 chimeric constructs were created and used to rescue V2−/− fibroblasts. Surprisingly, the commonly cited V2-specific N-terminal extension and cysteines were found to be dispensable for Bak import and high tBid sensitivity. In gain-of-function studies, V2 (123–179) was the minimal sequence sufficient to render V1 competent to support Bak insertion. Furthermore, in loss-of-function experiments, T168 and D170 were identified as critical residues. These motifs are conserved in zebrafish V2 (zfV2) that also rescued V2-deficient fibroblasts. Because high-resolution structures of zfV2 and mammalian V1 have become available, we could superimpose these structures and recognized that the critical V2-specific residues help to create a distinctive open “pocket” on the cytoplasmic surface that could facilitate Bak recruitment.

scholarly journals Structure of the human voltage-dependent anion channel

2008 ◽  
Vol 105 (40) ◽  
pp. 15370-15375 ◽  
Author(s):  
Monika Bayrhuber ◽  
Thomas Meins ◽  
Michael Habeck ◽  
Stefan Becker ◽  
Karin Giller ◽  
...  
Keyword(s):  
Metabolic Flux ◽  
3D Structure ◽  
Anion Channel ◽  
Bioinformatic Analysis ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
X Ray Crystallography ◽  
Voltage Dependent ◽  
Α Helix ◽  
Induced Apoptosis

The voltage-dependent anion channel (VDAC), also known as mitochondrial porin, is the most abundant protein in the mitochondrial outer membrane (MOM). VDAC is the channel known to guide the metabolic flux across the MOM and plays a key role in mitochondrially induced apoptosis. Here, we present the 3D structure of human VDAC1, which was solved conjointly by NMR spectroscopy and x-ray crystallography. Human VDAC1 (hVDAC1) adopts a β-barrel architecture composed of 19 β-strands with an α-helix located horizontally midway within the pore. Bioinformatic analysis indicates that this channel architecture is common to all VDAC proteins and is adopted by the general import pore TOM40 of mammals, which is also located in the MOM.

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 Bax interacts with the voltage-dependent anion channel and mediates ethanol-induced apoptosis in rat hepatocytes

2004 ◽  
Vol 287 (3) ◽  
pp. G695-G705 ◽  
Author(s):  
Masayuki Adachi ◽  
Hajime Higuchi ◽  
Soichiro Miura ◽  
Toshifumi Azuma ◽  
Sayaka Inokuchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Anion Channel ◽  
Rat Hepatocytes ◽  
Hepatocyte Apoptosis ◽  
Voltage Dependent Anion Channel ◽  
Subsequent Formation ◽  
Voltage Dependent ◽  
Acute Ethanol ◽  
Induced Apoptosis ◽  
Stress Dependent

Acute ethanol exposure induces oxidative stress and apoptosis in primary rat hepatocytes. Previous data indicate that the mitochondrial permeability transition (MPT) is essential for ethanol-induced apoptosis. However, the mechanism by which ethanol induces the MPT remains unclear. In this study, we investigated the role of Bax, a proapoptotic Bcl-2 family protein, in acute ethanol-induced hepatocyte apoptosis. We found that Bax translocates from the cytosol to mitochondria before mitochondrial cytochrome c release. Bax translocation was oxidative stress dependent. Mitochondrial Bax formed a protein complex with the mitochondrial voltage-dependent anion channel (VDAC). Prevention of Bax-VDAC interactions by a microinjection of anti-VDAC antibody effectively prevented hepatocyte apoptosis by ethanol. In conclusion, these data suggest that Bax translocation from the cytosol to mitochondria leads to the subsequent formation of a Bax-VDAC complex that plays a crucial role in acute ethanol-induced hepatocyte apoptosis.

scholarly journals Essential Role of Voltage-Dependent Anion Channel in Various Forms of Apoptosis in Mammalian Cells

2001 ◽  
Vol 152 (2) ◽  
pp. 237-250 ◽  
Author(s):  
Shigeomi Shimizu ◽  
Yosuke Matsuoka ◽  
Yasuo Shinohara ◽  
Yoshihiro Yoneda ◽  
Yoshihide Tsujimoto
Keyword(s):  
Cytochrome C ◽  
Mammalian Cells ◽  
Essential Role ◽  
Biological Significance ◽  
Anion Channel ◽  
Voltage Dependent Anion Channel ◽  
Cytochrome C Release ◽  
Isolated Mitochondria ◽  
Voltage Dependent ◽  
Induced Apoptosis

Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic members of the Bcl-2 family such as Bax and Bak induce apoptogenic cytochrome c release in isolated mitochondria, whereas BH3-only proteins such as Bid and Bik do not directly target the VDAC to induce cytochrome c release. To investigate the biological significance of the VDAC for apoptosis in mammalian cells, we produced two kinds of anti-VDAC antibodies that inhibited VDAC activity. In isolated mitochondria, these antibodies prevented Bax-induced cytochrome c release and loss of the mitochondrial membrane potential (Δψ), but not Bid-induced cytochrome c release. When microinjected into cells, these anti-VDAC antibodies, but not control antibodies, also prevented Bax-induced cytochrome c release and apoptosis, whereas the antibodies did not prevent Bid-induced apoptosis, indicating that the VDAC is essential for Bax-induced, but not Bid-induced, apoptogenic mitochondrial changes and apoptotic cell death. In addition, microinjection of these anti-VDAC antibodies significantly inhibited etoposide-, paclitaxel-, and staurosporine-induced apoptosis. Furthermore, we used these antibodies to show that Bax- and Bak-induced lysis of red blood cells was also mediated by the VDAC on plasma membrane. Taken together, our data provide evidence that the VDAC plays an essential role in apoptogenic cytochrome c release and apoptosis in mammalian cells.

scholarly journals Calcium Flux between the Endoplasmic Reticulum and Mitochondrion Contributes to Poliovirus-Induced Apoptosis

2010 ◽  
Vol 84 (23) ◽  
pp. 12226-12235 ◽  
Author(s):  
Cynthia Brisac ◽  
François Téoulé ◽  
Arnaud Autret ◽  
Isabelle Pelletier ◽  
Florence Colbère-Garapin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mitochondrial Dysfunction ◽  
Ryanodine Receptor ◽  
Anion Channel ◽  
Cytosolic Calcium ◽  
Calcium Flux ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Infected Cells ◽  
Induced Apoptosis

ABSTRACT We show that poliovirus (PV) infection induces an increase in cytosolic calcium (Ca2+) concentration in neuroblastoma IMR5 cells, at least partly through Ca2+ release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This leads to Ca2+ accumulation in mitochondria through the mitochondrial Ca2+ uniporter and the voltage-dependent anion channel (VDAC). This increase in mitochondrial Ca2+ concentration in PV-infected cells leads to mitochondrial dysfunction and apoptosis.

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.

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