scholarly journals Evidences of a Direct Relationship between Cellular Fuel Supply and Ciliogenesis Regulated by Hypoxic VDAC1-ΔC

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3484
Author(s):  
Monique Meyenberg Cunha-de Padua ◽  
Lucilla Fabbri ◽  
Maeva Dufies ◽  
Sandra Lacas-Gervais ◽  
Julie Contenti ◽  
...  
Keyword(s):  
Direct Relationship ◽  
Cell Metabolism ◽  
Genetic Disorders ◽  
Phosphorylation Site ◽  
Anion Channel ◽  
Metabolic Flexibility ◽  
Apoptosis Resistance ◽  
Voltage Dependent Anion Channel ◽  
Putative Phosphorylation Site ◽  
Voltage Dependent

Metabolic flexibility is the ability of a cell to adapt its metabolism to changes in its surrounding environment. Such adaptability, combined with apoptosis resistance provides cancer cells with a survival advantage. Mitochondrial voltage-dependent anion channel 1 (VDAC1) has been defined as a metabolic checkpoint at the crossroad of these two processes. Here, we show that the hypoxia-induced cleaved form of VDAC1 (VDAC1-ΔC) is implicated in both the up-regulation of glycolysis and the mitochondrial respiration. We demonstrate that VDAC1-ΔC, due to the loss of the putative phosphorylation site at serine 215, concomitantly with the loss of interaction with tubulin and microtubules, reprograms the cell to utilize more metabolites, favoring cell growth in hypoxic microenvironment. We further found that VDAC1-ΔC represses ciliogenesis and thus participates in ciliopathy, a group of genetic disorders involving dysfunctional primary cilium. Cancer, although not representing a ciliopathy, is tightly linked to cilia. Moreover, we highlight, for the first time, a direct relationship between the cilium and cancer cell metabolism. Our study provides the first new comprehensive molecular-level model centered on VDAC1-ΔC integrating metabolic flexibility, ciliogenesis, and enhanced survival in a hypoxic microenvironment.

scholarly journals VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1485 ◽  
Author(s):  
Varda Shoshan-Barmatz ◽  
Anna Shteinfer-Kuzmine ◽  
Ankit Verma
Keyword(s):  
Cell Metabolism ◽  
Anion Channel ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Pathological Conditions ◽  
Large Channel ◽  
Voltage Dependent ◽  
Important Regulator ◽  
Apoptotic Proteins ◽  
Interferon Responses

The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.

Abstract 851: The Cardioprotective Effect Of Glycogen Synthase Kinase-3β (gsk-3β) Inhibitors Involves Inhibition Of Mitochondrial Adenine Nucleotide Transport

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Samarjit Das ◽  
Elizabeth Murphy ◽  
Charles Steenbergen
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Glycogen Synthase ◽  
Adenine Nucleotide ◽  
Ischemia Reperfusion ◽  
Phosphorylation Site ◽  
Anion Channel ◽  
Left Ventricular ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Gsk 3Β

Inhibition of GSK-3β has been shown to reduce ischemia-reperfusion injury by acting on the mitochondria. We aimed to determine the mechanism by which inhibition of GSK-3β mediates cardioprotection. Rats were treated with specific GSK-3β inhibitors, SB216763 (3 μM) or SB415286 (10 μM) 15 min prior to ischemia. Both inhibitors significantly improved post-ischemic left ventricular function after 20 minutes of ischemia compared to control. Mitochondria were isolated from all three groups of hearts immediately after 15 min perfusion with/without GSK-3β inhibitors. Both the SB compounds significantly reduced state 3 respiration as well as ATP consumption during anoxia. Consumption of ATP during anoxia was measured by allowing mitochondria in an oxygraph chamber to consume oxygen until they became anoxic, and the rate of consumption of added ATP was measured at 20, 40, and 60 minutes of anoxia. GSK-3β inhibitors significantly slowed anoxic mitochondrial ATP consumption. Similarly, GSK-3β inhibitors significantly reduced ATP consumption when sodium cyanide was used to stop mitochondrial respiration and also when the mitochondria were deenergized by uncoupler addition. This reduction in ATP consumption could be due to inhibition of ATP entry into the mitochondria through Voltage dependent anion channel (VDAC) and/or the adenine nucleotide transporter (ANT), inhibition of some other unknown protein which may directly inhibit mitochondrial transport, or inhibition of the F1F0 ATPase. To identify proteins that might be involved in this reduced ATP consumption, western blot analysis with phospho-Akt substrate antibody and 1-D gel phosphorylation site analysis staining revealed the GSK-3β inhibitors significantly decrease the phosphorylation of a 32 kDa protein compared to control mitochondria. We then cut out the 32 kDa band and used mass spectrometry to identify proteins. Voltage dependent anion channel members 1, 2 and 3 were all identified along with the adenine nucleotide translocator and γ-subunit of the F1 ATPase. Taken together the data indicate that GSK-3β regulates mitochondrial energetics under anoxic conditions, which may play an important role in cardioprotection.

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 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.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

Abstract 189: Activation of Voltage-Dependent Anion Channel 2 Suppresses Ca 2+ -Induced Cardiac Arrhythmia

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jaunian Chen ◽  
Johann Schredelseker ◽  
Hirohito Shimizu ◽  
Jie Huang ◽  
Kui Lu ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cardiac Arrhythmia ◽  
Critical Role ◽  
Anion Channel ◽  
Cardiac Contraction ◽  
Voltage Dependent Anion Channel ◽  
Rescue Effect ◽  
Cardiac Fibrillation ◽  
Wide Range ◽  
Voltage Dependent

Abnormal Ca2+ handling in cardiac muscle cells is associated with a wide range of human cardiac diseases, including heart failure and cardiac arrhythmias. Zebrafish tremblor (tre) mutant embryos manifest unsynchronized cardiac contractions due to a Ca2+ extrusion defect in cardiomyocytes and thus are used as an animal model for aberrant Ca2+ homeostasis-induced cardiac arrhythmia. To further dissect molecular mechanisms regulating cardiac Ca2+ homeostasis, we conducted a chemical suppressor screen on tre and found that efsevin, a synthetic compound, potently suppresses cardiac fibrillation and restores rhythmic cardiac contractions in tre embryos. In addition, the treatment with efsevin blocks the propagation of arrhythmogenic Ca2+ waves and accelerates the decay phase of Ca2+ sparks in adult murine cardiomyocytes under Ca2+ overload conditions, demonstrating that efsevin modulates Ca2+ handling in both embryonic and adult cardiac tissues. Through a biochemical pulldown assay, we identified a direct interaction between efsevin and VDAC2, a mitochondrial outer membrane voltage dependent anion channel. Overexpression of VDAC2 restores synchronized cardiac contraction in tre and knocking down VDAC2 activity abolishes the rescue effect of efsevin on tre, suggesting that efsevin modulates cardiac Ca2+ homeostasis by potentiating VDAC2 activity. We further showed that enhancing mitochondria Ca2+ uptake by overexpressing MICU or MCU suppresses cardiac fibrillation in tre just like VDAC2 does. Interestingly, this suppressive effect is absent in tre/vdac2 double deficient embryos and co-expression of VDAC2 and MICU or MCU results in synergistic rescue effect on tre, indicating a critical role for mitochondria in regulating cardiac Ca2+ handling and rhythmicity and suggesting that VDAC2 functions as a gate for transporting Ca2+ across the outer membrane. Taken together, our findings identify efsevin as a potent pharmacological tool to modulate cardiac Ca2+ handling, suggest a critical role of mitochondria in the control of cardiac rhythmicity and establish VDAC2 as a modulator of cardiac Ca2+ handling and a potential therapeutic target for the treatment of arrhythmias.

Sign in / Sign up

Export Citation Format

Share Document