scholarly journals Response of yeast to the regulated expression of proteins in the Bcl-2 family

2003 ◽  
Vol 374 (2) ◽  
pp. 393-402 ◽  
Author(s):  
Peter POLČIC ◽  
Michael FORTE
Keyword(s):  
Family Member ◽  
Mammalian Cells ◽  
Family Members ◽  
Anion Channel ◽  
Functional Responses ◽  
Voltage Dependent Anion Channel ◽  
Antagonistic Action ◽  
Mitochondrial Target ◽  
Voltage Dependent ◽  
Apoptotic Cascade

The mechanisms by which pro-apoptotic members of the Bcl-2 family of proteins promote the release of mitochondrial factors like cytochrome c, subsequently activating the apoptotic cascade, or by which anti-apoptotic family members block this release, are still not understood. When expressed in yeast, Bcl-2 family members act directly upon conserved mitochondrial components that correspond to their apoptotic substrates in mammalian cells. Here we describe a system in which the levels of representative pro- and anti-apoptotic members of the Bcl-2 family can be regulated independently in yeast. Using this system, we have focused on the action of the anti-apoptotic family member Bcl-xL, and have defined the quantitative relationships that underlie the antagonistic action of this protein on the lethal consequences of expression of the pro-apoptotic family member Bax. This system has also allowed us to demonstrate biochemically that Bcl-xL has two actions at the level of the mitochondrion. Bcl-xL is able to inhibit the stable integration of Bax into mitochondrial membranes, as well as hinder the action of Bax that does become stably integrated into these membranes. Taken together, our results suggest that both the functional and biochemical actions of Bcl-xL may be based on the ability of this molecule to disrupt the interaction of Bax with a resident mitochondrial target that is required for Bax action. Finally, we confirm that VDAC (voltage-dependent anion channel) is not required for the functional responses observed following the expression of either pro- or anti-apoptotic members of the Bcl-2 family.

scholarly journals Depletion of a Toxoplasma porin leads to defects in mitochondrial morphology and contacts with the ER

2021 ◽  
Author(s):  
Natalia Mallo ◽  
Jana Ovciarikova ◽  
Erica S. Martins-Duarte ◽  
Stephan C. Baehr ◽  
Marco Biddau ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Protein Import ◽  
Morphological Changes ◽  
Anion Channel ◽  
Multiple Roles ◽  
Mitochondrial Morphology ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Molecule Transport ◽  
Small Molecule Transport

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

scholarly journals Depletion of voltage-dependent anion channel (VDAC) of Toxoplasma gondii affects multiple mitochondrial functions, but not calcium signalling

2020 ◽  
Author(s):  
Natalia Mallo ◽  
Erica S. Martins Duarte ◽  
Stephan C. Baehr ◽  
Marco Biddau ◽  
Jana Ovciarikova ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mammalian Cells ◽  
Protein Import ◽  
Morphological Changes ◽  
Calcium Signalling ◽  
Anion Channel ◽  
Voltage Dependent Anion Channel ◽  
Mitochondrial Functions ◽  
Voltage Dependent ◽  
Molecule Transport

AbstractThe Voltage Dependent Anion channel (VDAC) is a ubiquitous channel in the outer membrane of the mitochondrion with multiple roles in protein, metabolite and small molecule transport. In mammalian cells, VDAC, as part of a larger complex including the inositol triphosphate receptor, has been shown to have a role in mediating contact between the mitochondria and ER. We identify VDAC of the pathogenic apicomplexan Toxoplasma gondii and demonstrate its importance for parasite growth. We show that VDAC is involved in protein import and metabolite transfer to the mitochondria, but does not appear to modulate calcium (Ca2+) signalling. Further, depletion of VDAC resulted in significant morphological changes of the mitochondrion and ER, suggesting a role in mediating contacts between these organelles in T. gondii.

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 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 Biochemical and Genetic Analysis of the Mitochondrial Response of Yeast to BAX and BCL-XL

2000 ◽  
Vol 20 (9) ◽  
pp. 3125-3136 ◽  
Author(s):  
Atan Gross ◽  
Kirsten Pilcher ◽  
Elizabeth Blachly-Dyson ◽  
Emy Basso ◽  
Jennifer Jockel ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Genome ◽  
Atp Synthase ◽  
Mitochondrial Permeability Transition ◽  
Family Members ◽  
Growth Arrest ◽  
Anion Channel ◽  
Cell Killing ◽  
Β Subunit ◽  
Voltage Dependent Anion Channel

ABSTRACT The BCL-2 family includes both proapoptotic (e.g., BAX and BAK) and antiapoptotic (e.g., BCL-2 and BCL-XL) molecules. The cell death-regulating activity of BCL-2 members appears to depend on their ability to modulate mitochondrial function, which may include regulation of the mitochondrial permeability transition pore (PTP). We examined the function of BAX and BCL-XL using genetic and biochemical approaches in budding yeast because studies with yeast suggest that BCL-2 family members act upon highly conserved mitochondrial components. In this study we found that in wild-type yeast, BAX induced hyperpolarization of mitochondria, production of reactive oxygen species, growth arrest, and cell death; however, cytochrome c was not released detectably despite the induction of mitochondrial dysfunction. Coexpression of BCL-XL prevented all BAX-mediated responses. We also assessed the function of BCL-XL and BAX in the same strain of Saccharomyces cerevisiae with deletions of selected mitochondrial proteins that have been implicated in the function of BCL-2 family members. BAX-induced growth arrest was independent of the tested mitochondrial components, including voltage-dependent anion channel (VDAC), the catalytic β subunit or the δ subunit of the F0F1-ATP synthase, mitochondrial cyclophilin, cytochrome c, and proteins encoded by the mitochondrial genome as revealed by [rho 0] cells. In contrast, actual cell killing was dependent upon select mitochondrial components including the β subunit of ATP synthase and mitochondrial genome-encoded proteins but not VDAC. The BCL-XL protection from either BAX-induced growth arrest or cell killing proved to be independent of mitochondrial components. Thus, BAX induces two cellular processes in yeast which can each be abrogated by BCL-XL: cell arrest, which does not require aspects of mitochondrial biochemistry, and cell killing, which does.

scholarly journals Identification of two voltage-dependent anion channel-like protein sequences conserved in Kinetoplastida

2012 ◽  
Vol 8 (3) ◽  
pp. 446-449 ◽  
Author(s):  
Nadine Flinner ◽  
Enrico Schleiff ◽  
Oliver Mirus
Keyword(s):  
Outer Membrane ◽  
Trypanosoma Brucei ◽  
Protein Sequences ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

The eukaryotic porin superfamily consists of two families, voltage-dependent anion channel (VDAC) and Tom40, which are both located in the mitochondrial outer membrane. In Trypanosoma brucei , only a single member of the VDAC family has been described. We report the detection of two additional eukaryotic porin-like sequences in T. brucei . By bioinformatic means, we classify both as putative VDAC isoforms.

Bcl-2 Family of Proteins: Life-or-Death Switch in Mitochondria

2002 ◽  
Vol 22 (1) ◽  
pp. 47-58 ◽  
Author(s):  
Yoshihide Tsujimoto
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Apoptotic Cell ◽  
Regulatory Protein ◽  
Family Members ◽  
Anion Channel ◽  
Permeability Transition ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Membrane Barrier

An increase in the permeability of outer mitochondrial membrane is central to apoptotic cell death, and results in the release of several apoptogenic factors such as cytochrome c into the cytoplasm to activate downstream destructive programs. The voltage-dependent anion channel (VDAC or mitochondrial porin) plays an essential role in disrupting the mitochondrial membrane barrier and is regulated directly by members of the Bcl-2 family proteins. Anti-apoptotic Bcl-2 family members interact with and close the VDAC, whereas some, but not all, proapoptotic members interact with VDAC to open protein-conducting pore through which apoptogenic factors pass. Although the VDAC is involved directly in breaking the mitochondrial membrane barrier and is a known component of the permeability transition pore complex, VDAC-dependent increase in outer membrane permeability can be independent of the permeability transition event such as mitochondrial swelling followed by rupture of the outer mitochondrial membrane. VDAC interacts not only with Bcl-2 family members but also with proteins such as gelsolin, an actin regulatory protein, and appears to be a convergence point for a variety of cell survival and cell death signals.

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