scholarly journals Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels

2006 ◽  
Vol 175 (6) ◽  
pp. 901-911 ◽  
Author(s):  
György Szabadkai ◽  
Katiuscia Bianchi ◽  
Péter Várnai ◽  
Diego De Stefani ◽  
Mariusz R. Wieckowski ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Fate ◽  
Recombinant Expression ◽  
Control Point ◽  
Anion Channel ◽  
Cellular Functions ◽  
Voltage Dependent Anion Channel ◽  
Release Channel ◽  
Voltage Dependent ◽  
Trisphosphate Receptor

The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca2+, and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum Ca2+-release channel inositol 1,4,5-trisphosphate receptor (IP3R) through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was shown by the recombinant expression of the ligand-binding domain of the IP3R on the ER or mitochondrial surface, which directly enhanced Ca2+ accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP3R and the mitochondrial Ca2+ uptake machinery. Because organelle Ca2+ homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis.

Moving Ca2+ from the endoplasmic reticulum to mitochondria: is spatial intimacy enough?

2006 ◽  
Vol 34 (3) ◽  
pp. 351-355 ◽  
Author(s):  
G.A. Rutter
Keyword(s):  
Endoplasmic Reticulum ◽  
Outer Membrane Proteins ◽  
Anion Channel ◽  
Mitochondrial Outer Membrane ◽  
Interconnected Network ◽  
Voltage Dependent Anion Channel ◽  
Permeabilized Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Voltage Dependent ◽  
Trisphosphate Receptor

A number of studies in recent years have demonstrated that the ER (endoplasmic reticulum) makes intimate contacts with mitochondria, the latter organelles existing both as individual organelles and occasionally as a more extensive interconnected network. Demonstrations that mitochondria take up Ca2+ more avidly upon its mobilization from the ER than when delivered to permeabilized cells as a buffered solution also indicate that a shielded conduit for Ca2+ may exist between the two organelle types, perhaps comprising the inositol 1,4,5-trisphosphate receptor and mitochondrial outer membrane proteins including the VDAC (voltage-dependent anion channel). Although the existence of such intracellular ER–mitochondria ‘synapses’, or of an ER–mitochondria Ca2+ ‘translocon’, is an exciting idea, more definitive experiments are needed to test this possibility.

scholarly journals Involvement of the IP3R-Grp75-VDAC1-MCU calcium axis in proteinuria in adriamycin-induced nephropathy rats

2019 ◽  
Author(s):  
Sisi Wang ◽  
Han Xu ◽  
Na Guan ◽  
Qijiao Wei ◽  
Yinghong Tao ◽  
...  
Keyword(s):  
Anion Channel ◽  
Ruthenium Red ◽  
Voltage Dependent Anion Channel ◽  
Podocyte Injury ◽  
Inositol 1 ◽  
Calcium Uniporter ◽  
Voltage Dependent ◽  
Trisphosphate Receptor ◽  
Glucose Regulated Protein

Abstract Background Podocyte injury plays a key role in the development of proteinuria. We previously found that the intracellular inositol 1, 4, 5-trisphosphate receptor (IP3R)- glucose-regulated protein 75 (Grp75)- voltage dependent anion channel 1 (VDAC1)- mitochondrial calcium uniporter (MCU) calcium axis contributes to podocyte injury in cultured mouse podocytes. Objective This study investigated whether the IP3R-Grp75-VDAC1-MCU calcium axis is involved in the development and improvement of proteinuria in nephropathy rats.Methods The expression of members of the IP3R-Grp75-VDAC1-MCU calcium axis in the renal cortex of a previously established adriamycin (ADR)-induced nephropathy rat model and cultured mouse podocytes was investigated by western blot analysis and immunohistochemical staining. The effects of ruthenium red (RR), an MCU inhibitor, oninteractions in the IP3R-Grp75-VDAC1-MCU calcium axis were investigated by in vitro co-immunoprecipitation assays.Results The overexpression and inhibition of members of the glomerular IP3R-Grp75-VDAC1-MCU calcium axis were accompanied by the development and improvement of proteinuria, respectively, in nephropathy rats. RR inhibited the upregulation of members of the IP3R-Grp75-VDAC1-MCU calcium axis induced by ADR and their interactions. Conclusions The IP3R-Grp75-VDAC1-MCU calcium axis is involved in proteinuria in ADR-induced nephropathy and can be inhibited by RR.

In the absence of phosphate shuttling, exercise reveals the in vivo importance of creatine-independent mitochondrial ADP transport

2016 ◽  
Vol 473 (18) ◽  
pp. 2831-2843 ◽  
Author(s):  
Paula M. Miotto ◽  
Graham P. Holloway
Keyword(s):  
Energy Homeostasis ◽  
Adenine Nucleotide ◽  
Control Point ◽  
Anion Channel ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Glycolytic Flux ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent

The transport of cytosolic adenosine diphosphate (ADP) into the mitochondria is a major control point in metabolic homeostasis, as ADP concentrations directly affect glycolytic flux and oxidative phosphorylation rates within mitochondria. A large contributor to the efficiency of this process is thought to involve phosphocreatine (PCr)/Creatine (Cr) shuttling through mitochondrial creatine kinase (Mi-CK), whereas the biological importance of alterations in Cr-independent ADP transport during exercise remains unknown. Therefore, we utilized an Mi-CK knockout (KO) model to determine whether in vivo Cr-independent mechanisms are biologically important for sustaining energy homeostasis during exercise. Ablating Mi-CK did not alter exercise tolerance, as the time to volitional fatigue was similar between wild-type (WT) and KO mice at various exercise intensities. In addition, skeletal muscle metabolic profiles after exercise, including glycogen, PCr/Cr ratios, free ADP/adenosine monophosphate (AMP), and lactate, were similar between genotypes. While these data suggest that the absence of PCr/Cr shuttling is not detrimental to maintaining energy homeostasis during exercise, KO mice displayed a dramatic increase in Cr-independent mitochondrial ADP sensitivity after exercise. Specifically, whereas mitochondrial ADP sensitivity decreased with exercise in WT mice, in stark contrast, exercise increased mitochondrial Cr-independent ADP sensitivity in KO mice. As a result, the apparent ADP Km was 50% lower in KO mice after exercise, suggesting that in vivo activation of voltage-dependent anion channel (VDAC)/adenine nucleotide translocase (ANT) can support mitochondrial ADP transport. Altogether, we provide insight that Cr-independent ADP transport mechanisms are biologically important for regulating ADP sensitivity during exercise, while highlighting complex regulation and the plasticity of the VDAC/ANT axis to support adenosine triphosphate demand.

scholarly journals VDAC2-mediated regulation of calcium homeostasis in cardiomyocytes (a review)

2020 ◽  
Vol 27 (6) ◽  
pp. 164-174
Author(s):  
N. V. Schcetinina ◽  
A. A. Bolotskaia
Keyword(s):  
Cardiovascular Diseases ◽  
Drug Target ◽  
English Language ◽  
Anion Channel ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Voltage Dependent Anion Channel ◽  
Release Channel ◽  
Promising Agent ◽  
Voltage Dependent

Background. Cardiovascular diseases, especially in association with arrhythmias, remain a prevailing cause of death worldwide. Arrhythmia related to imbalanced Ca2+ homeostasis is triggered by aberrant spontaneous diastolic Ca2+ leak from sarcoplasmic reticulum through cardiac ryanodine receptor-Ca2+ release channel (RyR2). Voltage-dependent anion channel 2 (VDAC2) is the only mammalian specific isoform also carrying a specific cardiac function.Objectives. Description of VDAC2-mediated regulation of Ca2+ concentration in cardiomyocytes. Methods. Literature sources were mined in the MedLine/PubMed and eLibrary databases with keywords “heart AND calcium”, “heart AND VDAC2”, with a subsequent analysis.Results. From 36 English-language sources, 5 were included in the review. We summarise that potentiated VDAC2 promotes mitochondrial transport of Ca2+ ions, and suppression of the channel leads to Ca2+ imbalances. Efsevin renders the channel more cation-selective and downregulates Ca2+ concentration in diastole.Conclusion. VDAC2 comprises a potential drug target in therapy for severe arrhythmias. Efsevin is a promising agent for correcting abnormal Ca2+ transport in cardiomyocytes as an accelerator of mitochondrial Ca2+ uptake.

scholarly journals Involvement of the IP3R-Grp75-VDAC1-MCU calcium axis in proteinuria in adriamycin-induced nephropathy rats

2020 ◽  
Author(s):  
Si-Si Wang ◽  
Han Xu ◽  
Na Guan ◽  
Qi-Jiao Wei ◽  
Ying-Hong Tao ◽  
...  
Keyword(s):  
Anion Channel ◽  
Ruthenium Red ◽  
Voltage Dependent Anion Channel ◽  
Podocyte Injury ◽  
Inositol 1 ◽  
Calcium Uniporter ◽  
Voltage Dependent ◽  
Trisphosphate Receptor ◽  
Glucose Regulated Protein

Abstract Background: Podocyte injury plays a key role in the development of proteinuria. We previously found that the intracellular inositol 1, 4, 5-trisphosphate receptor (IP3R)- glucose-regulated protein 75 (Grp75)- voltage dependent anion channel 1 (VDAC1)- mitochondrial calcium uniporter (MCU) calcium axis contributes to podocyte injury in cultured mouse podocytes. This study investigated whether the IP3R-Grp75-VDAC1-MCU calcium axis is involved in the development and improvement of proteinuria in nephropathy rats. Methods: The expression of members of the IP3R-Grp75-VDAC1-MCU calcium axis in the renal cortex of a previously established adriamycin (ADR)-induced nephropathy rat model and cultured mouse podocytes was investigated by western blot analysis and immunohistochemical staining. The effects of ruthenium red (RR), an MCU inhibitor, on interactions in the IP3R-Grp75-VDAC1-MCU calcium axis were investigated by in vitro co-immunoprecipitation assays. Results: In adriamycin induced nephropathy rat, the expression of members of the glomerular IP3R-Grp75-VDAC1-MCU calcium axis increased significantly compared with the normal control rats. RR inhibited the upregulation of members of the IP3R-Grp75-VDAC1-MCU calcium axis induced by ADR and their interactions. Conclusion: The IP3R-Grp75-VDAC1-MCU calcium axis is involved in proteinuria in ADR-induced nephropathy and can be inhibited by RR.

scholarly journals Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria

2002 ◽  
Vol 159 (4) ◽  
pp. 613-624 ◽  
Author(s):  
Elena Rapizzi ◽  
Paolo Pinton ◽  
György Szabadkai ◽  
Mariusz R. Wieckowski ◽  
Grégoire Vandecasteele ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
High Speed ◽  
Recombinant Expression ◽  
Anion Channel ◽  
Fast Diffusion ◽  
Inner Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
High Speed Imaging ◽  
Physiological Relevance ◽  
Voltage Dependent

Although the physiological relevance of mitochondrial Ca2+ homeostasis is widely accepted, no information is yet available on the molecular identity of the proteins involved in this process. Here we analyzed the role of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane in the transmission of Ca2+ signals between the ER and mitochondria by measuring cytosolic and organelle [Ca2+] with targeted aequorins and Ca2+-sensitive GFPs. In HeLa cells and skeletal myotubes, the transient expression of VDAC enhanced the amplitude of the agonist-dependent increases in mitochondrial matrix Ca2+ concentration by allowing the fast diffusion of Ca2+ from ER release sites to the inner mitochondrial membrane. Indeed, high speed imaging of mitochondrial and cytosolic [Ca2+] changes showed that the delay between the rises occurring in the two compartments is significantly shorter in VDAC-overexpressing cells. As to the functional consequences, VDAC-overexpressing cells are more susceptible to ceramide-induced cell death, thus confirming that mitochondrial Ca2+ uptake plays a key role in the process of apoptosis. These results reveal a novel function for the widely expressed VDAC channel, identifying it as a molecular component of the routes for Ca2+ transport across the mitochondrial membranes.

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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