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A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells.
Rasmussen ML, Kline LA, Park KP, Ortolano NA, Romero-Morales AI, Anthony CC, Beckermann KE, Gama V
(2018) Stem Cell Reports 10: 684-692
MeSH Terms: Apoptosis, Cell Differentiation, Cell Line, Cellular Reprogramming, Humans, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membranes, Myeloid Cell Leukemia Sequence 1 Protein, Pluripotent Stem Cells, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added March 14, 2018
Human pluripotent stem cells (hPSCs) maintain a highly fragmented mitochondrial network, but the mechanisms regulating this phenotype remain unknown. Here, we describe a non-cell death function of the anti-apoptotic protein, MCL-1, in regulating mitochondrial dynamics and promoting pluripotency of stem cells. MCL-1 is induced upon reprogramming, and its inhibition or knockdown induces dramatic changes to the mitochondrial network as well as loss of the key pluripotency transcription factors, NANOG and OCT4. Aside from localizing at the outer mitochondrial membrane like other BCL-2 family members, MCL-1 is unique in that it also resides at the mitochondrial matrix in pluripotent stem cells. Mechanistically, we find MCL-1 to interact with DRP-1 and OPA1, two GTPases responsible for remodeling the mitochondrial network. Depletion of MCL-1 compromised the levels and activity of these key regulators of mitochondrial dynamics. Our findings uncover an unexpected, non-apoptotic function for MCL-1 in the maintenance of mitochondrial structure and stemness.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
Clustering of integrin α5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells.
Starchenko A, Graves-Deal R, Yang YP, Li C, Zent R, Singh B, Coffey RJ
(2017) Mol Biol Cell 28: 1288-1300
MeSH Terms: Antibodies, Cadherins, Cell Adhesion, Cell Culture Techniques, Cell Line, Tumor, Cell Polarity, Colorectal Neoplasms, Epithelial Cells, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5, Integrin alpha5beta1, Integrin beta1, Membrane Proteins, Membranes
Show Abstract · Added May 3, 2017
Apicobasolateral polarity is a fundamental property of epithelial cells, and its loss is a hallmark of cancer. Integrin-mediated contact with the extracellular matrix defines the basal surface, setting in motion E-cadherin-mediated cell-cell contact, which establishes apicobasolateral polarity. Role(s) for lateral integrins in this polarization process and the consequences of their disruption are incompletely understood. We show that addition of an integrin β1-activating monoclonal antibody, P4G11, to invasive colorectal cancer cells in three-dimensional type 1 collagen reverts the invasive phenotype and restores apicobasolateral polarity. P4G11 induces clustering of integrin α5β1 at lateral, intercellular surfaces. This leads to deposition and polymerization of fibronectin and recruitment of paxillin to sites of lateral integrin α5β1 clustering and is followed by tight junction formation, as determined by ZO-1 localization. Inducible elimination of integrin α5 abrogates the epithelial-organizing effects of P4G11. In addition, polymerization of fibronectin is required for the effects of P4G11, and addition of polymerized superfibronectin is sufficient to induce tight junction formation and apicobasolateral polarization. In the normal human colon, we show that integrin α5 localizes to the lateral membrane of terminally differentiated colonocytes and that integrin α5 staining may be reduced in colorectal cancer. Thus we propose a novel role for integrin α5β1 in regulating epithelial morphogenesis.
© 2017 Starchenko et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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16 MeSH Terms
A pH-Mediated Topological Switch within the N-Terminal Domain of Human Caveolin-3.
Kim JH, Schlebach JP, Lu Z, Peng D, Reasoner KC, Sanders CR
(2016) Biophys J 110: 2475-2485
MeSH Terms: Amino Acid Sequence, Caveolin 3, Circular Dichroism, Humans, Hydrogen-Ion Concentration, Membranes, Artificial, Micelles, Models, Molecular, Mutation, Nuclear Magnetic Resonance, Biomolecular, Phosphatidylglycerols, Protein Structure, Secondary, Solubility, Solutions
Show Abstract · Added November 21, 2018
Caveolins mediate the formation of caveolae, which are small omega-shaped membrane invaginations involved in a variety of cellular processes. There are three caveolin isoforms, the third of which (Cav3) is expressed in smooth and skeletal muscles. Mutations in Cav3 cause a variety of human muscular diseases. In this work, we characterize the secondary structure, dynamics, and topology of the monomeric form of the full-length lipidated protein. Cav3 consists of a series of membrane-embedded or surface-associated helical elements connected by extramembrane connecting loops or disordered domains. Our results also reveal that the N-terminal domain undergoes a large scale pH-mediated topological rearrangement between soluble and membrane-anchored forms. Considering that roughly one-third of pathogenic mutations in Cav3 influence charged residues located in this domain, we hypothesize that this transition is likely to be relevant to the molecular basis of Cav3-linked diseases. These results provide insight into the structure of Cav3 and set the stage for mechanistic investigations of the effects of pathogenic mutations.
Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
First Implantation of Silicon Nanopore Membrane Hemofilters.
Kensinger C, Karp S, Kant R, Chui BW, Goldman K, Yeager T, Gould ER, Buck A, Laneve DC, Groszek JJ, Roy S, Fissell WH
(2016) ASAIO J 62: 491-5
MeSH Terms: Animals, Dogs, Hemofiltration, Humans, Membranes, Artificial, Nanopores, Pilot Projects, Silicon, Thrombosis
Show Abstract · Added April 11, 2016
An implantable hemofilter for the treatment of kidney failure depends critically on the transport characteristics of the membrane and the biocompatibility of the membrane, cartridge, and blood conduits. A novel membrane with slit-shaped pores optimizes the trade-off between permeability and selectivity, enabling implanted therapy. Sustained (3-8) day function of an implanted parallel-plate hemofilter with minimal anticoagulation was achieved by considering biocompatibility at the subnanometer scale of chemical interactions and the millimeter scale of blood fluid dynamics. A total of 400 nm-thick polysilicon flat sheet membranes with 5-8 nm × 2 micron slit-shaped pores were surface-modified with polyethylene glycol. Hemofilter cartridge geometries were refined based on computational fluid dynamics models of blood flow. In an uncontrolled pilot study, silicon filters were implanted in six class A dogs. Cartridges were connected to the cardiovascular system by anastamoses to the aorta and inferior vena cava and filtrate was drained to collection pouches positioned in the peritoneum. Pain medicine and acetylsalicylic acid were administered twice daily until the hemofilters were harvested on postoperative days 3 (n = 2), 4 (n = 2), 5 (n = 1), and 8 (n = 1). No hemofilters were thrombosed. Animals treated for 5 and 8 days had microscopic fractures in the silicon nanopore membranes and 20-50 ml of transudative (albumin sieving coefficient θalb ~ 0.5 - 0.7) fluid in the collection pouches at the time of explant. Shorter experimental durations (3-4 days) resulted in filtration volumes similar to predictions based on mean arterial pressures and membrane hydraulic permeability and (θalb ~ 0.2 - 0.3), similar to preimplantation measurements. In conclusion, a detailed mechanistic and materials science attention to blood-material interactions allows implanted hemofilters to resist thrombosis. Additional testing is needed to determine optimal membrane characteristics and identify limiting factors in long-term implantation.
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9 MeSH Terms
Preliminary Diffusive Clearance of Silicon Nanopore Membranes in a Parallel Plate Configuration for Renal Replacement Therapy.
Kim S, Heller J, Iqbal Z, Kant R, Kim EJ, Durack J, Saeed M, Do L, Hetts S, Wilson M, Brakeman P, Fissell WH, Roy S
(2016) ASAIO J 62: 169-75
MeSH Terms: Animals, Equipment Design, Membranes, Artificial, Nanopores, Renal Dialysis, Silicon, Swine
Show Abstract · Added February 22, 2016
Silicon nanopore membranes (SNMs) with compact geometry and uniform pore size distribution have demonstrated a remarkable capacity for hemofiltration. These advantages could potentially be used for hemodialysis. Here, we present an initial evaluation of the SNM's mechanical robustness, diffusive clearance, and hemocompatibility in a parallel plate configuration. Mechanical robustness of the SNM was demonstrated by exposing membranes to high flows (200 ml/min) and pressures (1,448 mm Hg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25 ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4 hours in an extracorporeal porcine model. The pressure drop across the flow cell was 4.6 mm Hg at 200 ml/min. Mechanical testing showed that SNM could withstand up to 775.7 mm Hg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extracorporeal studies showed blood was successfully driven via the arterial-venous pressure differential without thrombus formation. Bare silicon showed increased cell adhesion with a 4.1-fold increase and 1.8-fold increase over polyethylene glycol (PEG)-coated surfaces for tissue plasminogen factor (t-PA) and platelet adhesion (CD41), respectively. These initial results warrant further design and development of a fully scaled SNM-based parallel plate dialyzer for renal replacement therapy.
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7 MeSH Terms
Life after MOMP.
Gama V, Deshmukh M
(2015) Mol Cell 58: 199-201
MeSH Terms: Animals, Apoptosis, DNA Damage, Genomic Instability, Humans, Mitochondrial Membranes
Show Abstract · Added October 26, 2015
In this and a recent issue of Molecular Cell, Liu et al. (2015) and Ichim et al. (2015) report that low levels of caspase activity triggered by limited mitochondrial outer membrane permeabilization (MOMP) promote genomic instability that drives tumorigenesis, providing a novel and unexpected link between these effectors of apoptosis and cancer initiation.
Copyright © 2015 Elsevier Inc. All rights reserved.
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6 MeSH Terms
Integrin β3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice.
Mazalouskas M, Jessen T, Varney S, Sutcliffe JS, Veenstra-VanderWeele J, Cook EH, Carneiro AM
(2015) Neuropsychopharmacology 40: 2015-24
MeSH Terms: Analysis of Variance, Animals, Antidepressive Agents, Biological Transport, Gene Expression Regulation, Humans, Infant, Integrin beta3, Mice, Mice, Transgenic, Neurons, Phosphopyruvate Hydratase, Polymorphism, Genetic, Raphe Nuclei, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors, Synaptic Membranes
Show Abstract · Added February 15, 2016
Converging lines of evidence have identified genetic interactions between the serotonin transporter (SERT) gene and ITGB3, which encodes the β3 subunit that forms the αIIbβ3 and αvβ3 integrin receptor complexes. Here we examine the consequences of haploinsufficiency in the mouse integrin β3 subunit gene (Itgb3) on SERT function and selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) effectiveness in vivo. Biochemical fractionation studies and immunofluorescent staining of murine brain slices reveal that αvβ3 receptors and SERTs are enriched in presynaptic membranes from several brain regions and that αvβ3 colocalizes with a subpopulation of SERT-containing synapses in raphe nuclei. Notably, we establish that loss of a single allele of Itgb3 in murine neurons is sufficient to decrease 5-HT uptake by SERT in midbrain synaptosomes. Pharmacological assays to elucidate the αvβ3-mediated mechanism of reduced SERT function indicate that decreased integrin β3 subunit expression scales down the population size of active SERT molecules and, as a consequence, lowers the effective dose of SSRIs. These data are consistent with the existence of a subpopulation of SERTs that are tightly modulated by integrin αvβ3 and significantly contribute to global SERT function at 5-HT synapses in the midbrain. Importantly, our screen of a normal human population for single nucleotide polymorphisms in human ITGB3 identified a variant associated with reductions in integrin β3 expression levels that parallel our mouse findings. Thus, polymorphisms in human ITGB3 may contribute to the differential responsiveness of select patients to SSRIs.
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18 MeSH Terms
Reovirus forms neo-organelles for progeny particle assembly within reorganized cell membranes.
Fernández de Castro I, Zamora PF, Ooms L, Fernández JJ, Lai CM, Mainou BA, Dermody TS, Risco C
(2014) MBio 5:
MeSH Terms: Animals, Cell Line, Humans, Inclusion Bodies, Viral, Intracellular Membranes, Microscopy, Electron, Transmission, Reoviridae, Virus Assembly, Virus Replication
Show Abstract · Added May 20, 2014
UNLABELLED - Most viruses that replicate in the cytoplasm of host cells form neo-organelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral replication proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release of progeny particles. Despite the importance of inclusion complexes in viral replication, there are key gaps in the knowledge of how these organelles form and mediate their functions. Reoviruses are nonenveloped, double-stranded RNA (dsRNA) viruses that serve as tractable experimental models for studies of dsRNA virus replication and pathogenesis. Following reovirus entry into cells, replication occurs in large cytoplasmic structures termed inclusions that fill with progeny virions. Reovirus inclusions are nucleated by viral nonstructural proteins, which in turn recruit viral structural proteins for genome replication and particle assembly. Components of reovirus inclusions are poorly understood, but these structures are generally thought to be devoid of membranes. We used transmission electron microscopy and three-dimensional image reconstructions to visualize reovirus inclusions in infected cells. These studies revealed that reovirus inclusions form within a membranous network. Viral inclusions contain filled and empty viral particles and microtubules and appose mitochondria and rough endoplasmic reticulum (RER). Immunofluorescence confocal microscopy analysis demonstrated that markers of the ER and ER-Golgi intermediate compartment (ERGIC) codistribute with inclusions during infection, as does dsRNA. dsRNA colocalizes with the viral protein σNS and an ERGIC marker inside inclusions. These findings suggest that cell membranes within reovirus inclusions form a scaffold to coordinate viral replication and assembly.
IMPORTANCE - Viruses alter the architecture of host cells to form an intracellular environment conducive to viral replication. This step in viral infection requires the concerted action of viral and host components and is potentially vulnerable to pharmacological intervention. Reoviruses form large cytoplasmic replication sites called inclusions, which have been described as membrane-free structures. Despite the importance of inclusions in the reovirus replication cycle, little is known about their formation and composition. We used light and electron microscopy to demonstrate that reovirus inclusions are membrane-containing structures and that the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment interact closely with these viral organelles. These findings enhance our understanding of the cellular machinery usurped by viruses to form inclusion organelles and complete an infectious cycle. This information, in turn, may foster the development of antiviral drugs that impede this essential viral replication step.
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9 MeSH Terms
Characterization and modeling of the oligomeric state and ligand binding behavior of purified translocator protein 18 kDa from Rhodobacter sphaeroides.
Li F, Xia Y, Meiler J, Ferguson-Miller S
(2013) Biochemistry 52: 5884-99
MeSH Terms: Amino Acid Sequence, Apoptosis, Binding, Competitive, Carrier Proteins, Cholesterol, Cryoelectron Microscopy, Crystallization, Isoquinolines, Membrane Proteins, Mitochondrial Membranes, Protein Multimerization, Protoporphyrins, Receptors, GABA-A, Rhodobacter sphaeroides, Sequence Alignment
Show Abstract · Added January 24, 2015
Translocator Protein 18 kDa (TSPO), previously known as the peripheral-type benzodiazepine receptor (PBR), is a mitochondrial outer membrane protein that has been identified as a key player in cholesterol and porphyrin transport, apoptotic signaling, and cancer development, as well as neurological inflammation and disease. Despite a number of TSPO ligands whose effects have been studied with respect to these varied biological activities, the nature of their interactions with TSPO and the molecular mechanism of their effects remain controversial, in part because of the lack of an atomic-resolution structure. We expressed and purified the homologue of mammalian TSPO from Rhodobacter sphaeroides (RsTSPO), as well as a mutant form in a proposed drug binding loop, RsTSPOW38C. We characterized their binding behaviors with endogenous ligands and a series of compounds that affect apoptosis by using a sensitive tryptophan fluorescence quenching assay. Our results show that RsTSPO behaves as a dimer in the purified state and binds with low micromolar affinity to many of these ligands, including retinoic acid, curcumin, and a known Bcl-2 inhibitor, gossypol, suggesting a possible direct role for TSPO in their regulation of apoptosis. A computational model of the RsTSPO dimer is constructed using EM-Fold, Rosetta, and a cryo-electron microscopy density map. Binding behaviors of known ligands are discussed in the context of the model with respect to regions that may be involved in binding.
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15 MeSH Terms
Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension.
Fessel JP, Flynn CR, Robinson LJ, Penner NL, Gladson S, Kang CJ, Wasserman DH, Hemnes AR, West JD
(2013) Am J Respir Cell Mol Biol 49: 778-87
MeSH Terms: Animals, Arterial Pressure, Bone Morphogenetic Protein Receptors, Type II, Cardiac Output, Cell Line, Tumor, Disease Models, Animal, Endothelial Cells, Familial Primary Pulmonary Hypertension, Humans, Hyperoxia, Hypertension, Pulmonary, Lung, Lung Injury, Mice, Mice, Transgenic, Mitochondria, Mitochondrial Membranes, Mutation, Oxidative Stress, Pulmonary Artery, Reactive Oxygen Species, Stress, Physiological, Ventricular Function, Right, Ventricular Pressure
Show Abstract · Added April 17, 2014
Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing mutation in bone morphogenic protein receptor 2 (Bmpr2) were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 h) for 6 weeks, and were compared with wild-type animals undergoing identical exposures. In both murine tissues and cultured endothelial cells, the expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With the enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These experiments demonstrate that oxidant injury and metabolic stress contribute directly to disease development, and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations.
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24 MeSH Terms