scholarly journals Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance

2020 ◽  
Vol 295 (43) ◽  
pp. 14653-14665
Author(s):  
Shashank Ranjan Srivastava ◽  
Radhakrishnan Mahalakshmi
Keyword(s):  
Functional Significance ◽  
Anion Channel ◽  
Dependent Manner ◽  
Structural Adaptation ◽  
Voltage Dependent Anion Channel ◽  
Voltage Dependent ◽  
Gated Channel ◽  
Engineered Structures ◽  
Transmembrane Transporters

Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd-stranded, i.e. 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel. Here, using the human voltage-dependent anion channel as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V216, V217, V218) and larger (V220, V221) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid-dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage-gated channel regulation, efficient mitochondrial targeting, and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.

scholarly journals Redox-dependent gating of VDAC by mitoNEET

2019 ◽  
Vol 116 (40) ◽  
pp. 19924-19929 ◽  
Author(s):  
Colin H. Lipper ◽  
Jason T. Stofleth ◽  
Fang Bai ◽  
Yang-Sung Sohn ◽  
Susmita Roy ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Anion Channel ◽  
Fatty Acid Transport ◽  
Dependent Manner ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Ros Homeostasis ◽  
Parkinson’S Diseases ◽  
Voltage Dependent

MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species (ROS) homeostasis. It is a key player in multiple human maladies including diabetes, cancer, neurodegeneration, and Parkinson’s diseases. In healthy cells, mitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins in a process that could be altered by drugs or during illness. Here, we report that mitoNEET regulates the outer-mitochondrial membrane (OMM) protein voltage-dependent anion channel 1 (VDAC1). VDAC1 is a crucial player in the cross talk between the mitochondria and the cytosol. VDAC proteins function to regulate metabolites, ions, ROS, and fatty acid transport, as well as function as a “governator” sentry for the transport of metabolites and ions between the cytosol and the mitochondria. We find that the redox-sensitive [2Fe-2S] cluster protein mitoNEET gates VDAC1 when mitoNEET is oxidized. Addition of the VDAC inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS) prevents both mitoNEET binding in vitro and mitoNEET-dependent mitochondrial iron accumulation in situ. We find that the DIDS inhibitor does not alter the redox state of MitoNEET. Taken together, our data indicate that mitoNEET regulates VDAC in a redox-dependent manner in cells, closing the pore and likely disrupting VDAC’s flow of metabolites.

Mitochondrial Protective Effects of Myrica rubra Extract Against Acetaminophen-Induced Toxicity

2013 ◽  
Vol 41 (05) ◽  
pp. 1053-1064 ◽  
Author(s):  
Wenwen Gou ◽  
Lizhi Xu ◽  
Yucai Wang ◽  
Wen Yu ◽  
Zengtao Zhong ◽  
...  
Keyword(s):  
Anion Channel ◽  
Hepatoprotective Activity ◽  
Dependent Manner ◽  
Protective Effects ◽  
Voltage Dependent Anion Channel ◽  
Myrica Rubra ◽  
Liver Histopathology ◽  
Voltage Dependent ◽  
Serum Aspartate Aminotransferase ◽  
Mice Liver

The present study investigates the hepatoprotective activity of Myrica rubra Sieb. et Zucc. extract (MCE) against acetaminophen (AAP)-induced liver damage and elucidates the possible mechanisms behind the hepatoprotection observed. Serum alanine aminotransferase and serum aspartate aminotransferase activities were detected and liver histopathology was observed. Mitochondrial swelling, mitochondrial membrane potential, and voltage-dependent anion channel (VDAC) gene transcription were also investigated. The results showed that 50, 150, and 450 mg/kg MCE could restore AAP-induced changes in mice liver in a dose-dependent manner. The mechanisms behind the hepatoprotective effects of MCE may be related to the mitochondrial protection of liver cells, especially of VDAC, an important protein on the outer membrane of the mitochondria.

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 A deep dive into VDAC1 conformational diversity using all-atom simulations provides new insights into the structural origin of the closed states

2021 ◽  
Author(s):  
Jordane Preto ◽  
Hubert Gorny ◽  
Isabelle Krimm
Keyword(s):  
Anion Channel ◽  
Voltage Dependent Anion Channel ◽  
Deep Dive ◽  
Accelerated Molecular Dynamics ◽  
Mitochondrial Transporter ◽  
Voltage Dependent ◽  
Key Factor ◽  
Gated Channel ◽  
Conformational Landscape ◽  
Transport Of Ions

The voltage-dependent anion channel 1 (VDAC1) is a crucial mitochondrial transporter which controls the flow of ions and respiratory metabolites entering or exiting mitochondria. As a voltage-gated channel, VDAC1 can switch between a high conducting "open" state and low conducting "closed" states emerging at high transmembrane potential. Although cell homeostasis depends on channel gating to regulate the transport of ions and metabolites, structural hallmarks characterizing the closed states remain unknown. Here we performed microsecond accelerated molecular dynamics to highlight a vast region of VDAC1 conformational landscape accessible at typical voltage known to promote closure. Conformers exhibiting stable subconducting properties inherent to closed states were identified. In all cases, the low conductance was due to the particular positioning of an unfolded part of the N-terminus which obstructed the channel pore. While the N-terminal tail was found to be sensitive to voltage orientation, our low-conducting models suggest that closed states predominantly take place from disordered events and do not result from the displacement of a voltage sensor or a significant change in the pore. In addition, our results were consistent with conductance jumps observed in experiments and corroborates a recent study describing entropy as a key factor for VDAC gating.

scholarly journals Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1

2019 ◽  
Author(s):  
Nicolas Tricaud ◽  
Benoit Gautier ◽  
Gerben Van Hameren ◽  
Jade Berthelot ◽  
Sergio Gonzalez ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Nerve Injury ◽  
Myelin Sheath ◽  
Calcium Release ◽  
Anion Channel ◽  
Mitochondrial Calcium ◽  
Voltage Dependent Anion Channel ◽  
Cellular Mechanisms ◽  
Voltage Dependent

AbstractThe maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.

scholarly journals The Open State Selectivity of the Bean Seed VDAC Depends on Stigmasterol and Ion Concentration

2021 ◽  
Vol 22 (6) ◽  
pp. 3034
Author(s):  
Hayet Saidani ◽  
Marc Léonetti ◽  
Hanna Kmita ◽  
Fabrice Homblé
Keyword(s):  
Physiological Role ◽  
Anion Channel ◽  
Physiological Effect ◽  
Ion Concentration ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Major Pathway ◽  
Voltage Dependent ◽  
State Selectivity

The voltage-dependent anion channel (VDAC) is the major pathway for metabolites and ions transport through the mitochondrial outer membrane. It can regulate the flow of solutes by switching to a low conductance state correlated with a selectivity reversal, or by a selectivity inversion of its open state. The later one was observed in non-plant VDACs and is poorly characterized. We aim at investigating the selectivity inversion of the open state using plant VDAC purified from Phaseolus coccineus (PcVDAC) to evaluate its physiological role. Our main findings are: (1) The VDAC selectivity inversion of the open state occurs in PcVDAC, (2) Ion concentration and stigmasterol affect the occurrence of the open state selectivity inversion and stigmasterol appears to interact directly with PcVDAC. Interestingly, electrophysiological data concerning the selectivity inversion of the PcVDAC open state suggests that the phenomenon probably does not have a significant physiological effect in vivo.

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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