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Regulation of ATP utilization during metastatic cell migration by collagen architecture.
Zanotelli MR, Goldblatt ZE, Miller JP, Bordeleau F, Li J, VanderBurgh JA, Lampi MC, King MR, Reinhart-King CA
(2018) Mol Biol Cell 29: 1-9
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Collagen, Extracellular Matrix, Female, Glucose, HEK293 Cells, Humans, Intracellular Space, Neoplasm Metastasis, Rats, Serum
Show Abstract · Added April 10, 2019
Cell migration in a three-dimensional matrix requires that cells either remodel the surrounding matrix fibers and/or squeeze between the fibers to move. Matrix degradation, matrix remodeling, and changes in cell shape each require cells to expend energy. While significant research has been performed to understand the cellular and molecular mechanisms guiding metastatic migration, less is known about cellular energy regulation and utilization during three-dimensional cancer cell migration. Here we introduce the use of the genetically encoded fluorescent biomarkers, PercevalHR and pHRed, to quantitatively assess ATP, ADP, and pH levels in MDA-MB-231 metastatic cancer cells as a function of the local collagen microenvironment. We find that the use of the probe is an effective tool for exploring the thermodynamics of cancer cell migration and invasion. Specifically, we find that the ATP:ADP ratio increases in cells in denser matrices, where migration is impaired, and it decreases in cells in aligned collagen matrices, where migration is facilitated. When migration is pharmacologically inhibited, the ATP:ADP ratio decreases. Together, our data indicate that matrix architecture alters cellular energetics and that intracellular ATP:ADP ratio is related to the ability of cancer cells to effectively migrate.
© 2018 Zanotelli, Goldblatt, Miller, 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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MeSH Terms
Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate.
Dixit S, Fessel JP, Harrison FE
(2017) Free Radic Biol Med 112: 515-523
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Antioxidants, Ascorbic Acid, Biological Transport, Disease Models, Animal, Female, Gene Expression Regulation, Heterozygote, Humans, Male, Membrane Potential, Mitochondrial, Mice, Mice, Transgenic, Mitochondria, Mutation, Oxidative Stress, Oxygen Consumption, Presenilin-1, Reactive Oxygen Species, Signal Transduction, Sodium-Coupled Vitamin C Transporters
Show Abstract · Added March 14, 2018
Mitochondrial dysfunction is elevated in very early stages of Alzheimer's disease and exacerbates oxidative stress, which contributes to disease pathology. Mitochondria were isolated from 4-month-old wild-type mice, transgenic mice carrying the APP and PSEN1 mutations, mice with decreased brain and mitochondrial ascorbate (vitamin C) via heterozygous knockout of the sodium dependent vitamin C transporter (SVCT2) and transgenic APP/PSEN1 mice with heterozygous SVCT2 expression. Mitochondrial isolates from SVCT2 mice were observed to consume less oxygen using high-resolution respirometry, and also exhibited decreased mitochondrial membrane potential compared to wild type isolates. Conversely, isolates from young (4 months) APP/PSEN1 mice consumed more oxygen, and exhibited an increase in mitochondrial membrane potential, but had a significantly lower ATP/ADP ratio compared to wild type isolates. Greater levels of reactive oxygen species were also produced in mitochondria isolated from both APP/PSEN1 and SVCT2 mice compared to wild type isolates. Acute administration of ascorbate to mitochondria isolated from wild-type mice increased oxygen consumption compared with untreated mitochondria suggesting ascorbate may support energy production. This study suggests that both presence of amyloid and ascorbate deficiency can contribute to mitochondrial dysfunction, even at an early, prodromal stage of Alzheimer's disease, although occurring via different pathways. Ascorbate may, therefore, provide a useful preventative strategy against neurodegenerative disease, particularly in populations most at risk for Alzheimer's disease in which stores are often depleted through mitochondrial dysfunction and elevated oxidative stress.
Copyright © 2017 Elsevier Inc. All rights reserved.
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25 MeSH Terms
Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy.
Litt MJ, Okoye GD, Lark D, Cakir I, Moore C, Barber MC, Atkinson J, Fessel J, Moslehi J, Cone RD
(2017) Elife 6:
MeSH Terms: Adenosine Diphosphate, Animals, Cardiomyopathy, Dilated, Cell Respiration, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Myocardium, Myocytes, Cardiac, Reactive Oxygen Species, Receptor, Melanocortin, Type 4
Show Abstract · Added December 2, 2017
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular disease. We show here that absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched diet induced obese mice do not display systolic dysfunction. cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from mice exhibited increased ADP stimulated respiratory capacity. However, this increase in respiration correlates with increased reactive oxygen species production - a canonical mediator of tissue damage. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure.
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11 MeSH Terms
Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis.
Plapp BV, Savarimuthu BR, Ferraro DJ, Rubach JK, Brown EN, Ramaswamy S
(2017) Biochemistry 56: 3632-3646
MeSH Terms: 2,2'-Dipyridyl, Adenosine Diphosphate Ribose, Alcohol Dehydrogenase, Animals, Catalytic Domain, Crystallography, X-Ray, Formamides, Horses, Kinetics, Liver, Models, Molecular, NAD, Phenanthrolines, Protein Binding, Protein Conformation, Water, Zinc
Show Abstract · Added August 31, 2017
During catalysis by liver alcohol dehydrogenase (ADH), a water bound to the catalytic zinc is replaced by the oxygen of the substrates. The mechanism might involve a pentacoordinated zinc or a double-displacement reaction with participation by a nearby glutamate residue, as suggested by studies of human ADH3, yeast ADH1, and some other tetrameric ADHs. Zinc coordination and participation of water in the enzyme mechanism were investigated by X-ray crystallography. The apoenzyme and its complex with adenosine 5'-diphosphoribose have an open protein conformation with the catalytic zinc in one position, tetracoordinated by Cys-46, His-67, Cys-174, and a water molecule. The bidentate chelators 2,2'-bipyridine and 1,10-phenanthroline displace the water and form a pentacoordinated zinc. The enzyme-NADH complex has a closed conformation similar to that of ternary complexes with coenzyme and substrate analogues; the coordination of the catalytic zinc is similar to that found in the apoenzyme, except that a minor, alternative position for the catalytic zinc is ∼1.3 Å from the major position and closer to Glu-68, which could form the alternative coordination to the catalytic zinc. Complexes with NADH and N-1-methylhexylformamide or N-benzylformamide (or with NAD and fluoro alcohols) have the classical tetracoordinated zinc, and no water is bound to the zinc or the nicotinamide rings. The major forms of the enzyme in the mechanism have a tetracoordinated zinc, where the carboxylate group of Glu-68 could participate in the exchange of water and substrates on the zinc. Hydride transfer in the Michaelis complexes does not involve a nearby water.
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17 MeSH Terms
Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor.
Oliver KH, Duvernay MT, Hamm HE, Carneiro AM
(2016) J Biol Chem 291: 20210-9
MeSH Terms: Adenosine Diphosphate, Animals, Blood Platelets, Citalopram, Female, Male, Mice, Mice, Knockout, Platelet Glycoprotein GPIIb-IIIa Complex, Receptor, Serotonin, 5-HT2A, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added October 26, 2016
Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERT(-/-)) of SERT function in vivo led to reduced serotonin (5-hydroxytryptamine (5-HT)) blood levels that paralleled a mild bleeding phenotype in mice. Transfusion of wild-type platelets to SERT(-/-) mice normalized bleeding times to wild-type levels, suggesting that loss of SERTs causes a deficiency in platelet activation. Although SERT(-/-) platelets displayed no difference in P-selectin or αIIbβ3 activation upon stimulation with thrombin, ADP-mediated αIIbβ3 activation is reduced in SERT(-/-) platelets. Additionally, synergistic potentiation of αIIbβ3 activation by ADP and 5-HT is lost in SERT(-/-) platelets. Acute treatment of wild-type platelets with 5-HT2A receptor (5-HT2AR) antagonists or SSRIs revealed that functional 5-HT2ARs, not SERTs, are necessary for the synergistic activation of αIIbβ3 by dual 5-HT/ADP stimulation. Pharmacological studies using radiolabeled guanosine 5'-3-O-([(35)S]thio)triphosphate and [(3)H]ketanserin revealed that platelets isolated from SERT(-/-) or citalopram-treated mice have reduced activation of G-proteins coupled to 5-HT2ARs and receptor surface expression. Taken together, these data demonstrate that sustained SERT loss of function reduces 5-HT2AR surface expression that is critical for the synergistic activation of αIIbβ3 by 5-HT and ADP. These results highlight an antiplatelet strategy centered on blocking or desensitizing 5-HT2AR to attenuate ADP-mediated αIIbβ3 activation.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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11 MeSH Terms
Direct real-time quantification of mitochondrial oxidative phosphorylation efficiency in permeabilized skeletal muscle myofibers.
Lark DS, Torres MJ, Lin CT, Ryan TE, Anderson EJ, Neufer PD
(2016) Am J Physiol Cell Physiol 311: C239-45
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Adenylate Kinase, Animals, Glucosephosphate Dehydrogenase, Hexokinase, Male, Mice, Mice, Inbred C57BL, Mitochondria, Muscle Fibers, Skeletal, NADP, Oxidative Phosphorylation, Oxygen Consumption
Show Abstract · Added October 17, 2016
Oxidative phosphorylation (OXPHOS) efficiency, defined as the ATP-to-O ratio, is a critical feature of mitochondrial function that has been implicated in health, aging, and disease. To date, however, the methods to measure ATP/O have primarily relied on indirect approaches or entail parallel rather than simultaneous determination of ATP synthesis and O2 consumption rates. The purpose of this project was to develop and validate an approach to determine the ATP/O ratio in permeabilized fiber bundles (PmFBs) from simultaneous measures of ATP synthesis (JATP) and O2 consumption (JO2 ) rates in real time using a custom-designed apparatus. JO2 was measured via a polarigraphic oxygen sensor and JATP via fluorescence using an enzyme-linked assay system (hexokinase II, glucose-6-phosphate dehydrogenase) linked to NADPH production. Within the dynamic linear range of the assay system, ADP-stimulated increases in steady-state JATP mirrored increases in steady-state JO2 (r(2) = 0.91, P < 0.0001, n = 57 data points). ATP/O ratio was less than one under low rates of respiration (15 μM ADP) but increased to more than two at moderate (200 μM ADP) and maximal (2,000 μM ADP) rates of respiration with an interassay coefficient of variation of 24.03, 16.72, and 11.99%, respectively. Absolute and relative (to mechanistic) ATP/O ratios were lower in PmFBs (2.09 ± 0.251, 84%) compared with isolated mitochondria (2.44 ± 0.124, 98%). ATP/O ratios in PmFBs were not affected by the activity of adenylate kinase or creatine kinase. These findings validate an enzyme-linked respiratory clamp system for measuring OXPHOS efficiency in PmFBs and provide evidence that OXPHOS efficiency increases as energy demand increases.
Copyright © 2016 the American Physiological Society.
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14 MeSH Terms
Wnt pathway activation by ADP-ribosylation.
Yang E, Tacchelly-Benites O, Wang Z, Randall MP, Tian A, Benchabane H, Freemantle S, Pikielny C, Tolwinski NS, Lee E, Ahmed Y
(2016) Nat Commun 7: 11430
MeSH Terms: Adenosine Diphosphate Ribose, Amino Acid Sequence, Animals, Animals, Genetically Modified, Axin Protein, Cell Line, Tumor, Drosophila Proteins, Drosophila melanogaster, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Lymphocytes, Molecular Sequence Data, Proteolysis, Sequence Alignment, Tankyrases, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Show Abstract · Added February 13, 2017
Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)--known to target Axin for proteolysis-regulates Axin's rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both Drosophila and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.
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21 MeSH Terms
Diminishing impairments in glucose uptake, mitochondrial content, and ADP-stimulated oxygen flux by mesenchymal stem cell therapy in the infarcted heart.
Hughey CC, James FD, Ma L, Bracy DP, Wang Z, Wasserman DH, Rottman JN, Shearer J
(2014) Am J Physiol Cell Physiol 306: C19-27
MeSH Terms: Adenosine Diphosphate, Animals, Glucose, Humans, Male, Mesenchymal Stem Cell Transplantation, Mice, Mice, Inbred C57BL, Mitochondria, Heart, Myocardial Contraction, Myocardial Infarction
Show Abstract · Added April 17, 2014
A constant provision of ATP is of necessity for cardiac contraction. As the heart progresses toward failure following a myocardial infarction (MI), it undergoes metabolic alterations that have the potential to compromise the ability to meet energetic demands. This study evaluated the efficacy of mesenchymal stem cell (MSC) transplantation into the infarcted heart to minimize impairments in the metabolic processes that contribute to energy provision. Seven and twenty-eight days following the MI and MSC transplantation, MSC administration minimized cardiac systolic dysfunction. Hyperinsulinemic-euglycemic clamps, coupled with 2-[(14)C]deoxyglucose administration, were employed to assess systemic insulin sensitivity and tissue-specific, insulin-mediated glucose uptake 36 days following the MI in the conscious, unrestrained, C57BL/6 mouse. The improved systolic performance in MSC-treated mice was associated with a preservation of in vivo insulin-stimulated cardiac glucose uptake. Conserved glucose uptake in the heart was linked to the ability of the MSC treatment to diminish the decline in insulin signaling as assessed by Akt phosphorylation. The MSC treatment also sustained mitochondrial content, ADP-stimulated oxygen flux, and mitochondrial oxidative phosphorylation efficiency in the heart. Maintenance of mitochondrial function and density was accompanied by preserved peroxisome proliferator-activated receptor-γ coactivator-1α, a master regulator of mitochondrial biogenesis. These studies provide insight into mechanisms of action that lead to an enhanced energetic state in the infarcted heart following MSC transplantation that may assist in energy provision and dampen cardiac dysfunction.
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11 MeSH Terms
Mitochondrial creatine kinase activity and phosphate shuttling are acutely regulated by exercise in human skeletal muscle.
Perry CG, Kane DA, Herbst EA, Mukai K, Lark DS, Wright DC, Heigenhauser GJ, Neufer PD, Spriet LL, Holloway GP
(2012) J Physiol 590: 5475-86
MeSH Terms: Adenosine Diphosphate, Animals, Creatine Kinase, Mitochondrial Form, Exercise, Humans, Male, Muscle Contraction, Muscle, Skeletal, Rats, Rats, Sprague-Dawley
Show Abstract · Added January 23, 2015
Energy transfer between mitochondrial and cytosolic compartments is predominantly achieved by creatine-dependent phosphate shuttling (PCr/Cr) involving mitochondrial creatine kinase (miCK). However, ADP/ATP diffusion through adenine nucleotide translocase (ANT) and voltage-dependent anion carriers (VDACs) is also involved in this process. To determine if exercise alters the regulation of this system, ADP-stimulated mitochondrial respiratory kinetics were assessed in permeabilized muscle fibre bundles (PmFBs) taken from biopsies before and after 2 h of cycling exercise (60% ) in nine lean males. Concentrations of creatine (Cr) and phosphocreatine (PCr) as well as the contractile state of PmFBs were manipulated in situ. In the absence of contractile signals (relaxed PmFBs) and miCK activity (no Cr), post-exercise respiratory sensitivity to ADP was reduced in situ (up to 126% higher apparent K(m) to ADP) suggesting inhibition of ADP/ATP diffusion between matrix and cytosolic compartments (possibly ANT and VDACs). However this effect was masked in the presence of saturating Cr (no effect of exercise on ADP sensitivity). Given that the role of ANT is thought to be independent of Cr, these findings suggest ADP/ATP, but not PCr/Cr, cycling through the outer mitochondrial membrane (VDACs) may be attenuated in resting muscle after exercise. In contrast, in contracted PmFBs, post-exercise respiratory sensitivity to ADP increased with miCK activation (saturating Cr; 33% lower apparent K(m) to ADP), suggesting prior exercise increases miCK sensitivity in situ. These observations demonstrate that exercise increases miCK-dependent respiratory sensitivity to ADP, promoting mitochondrial-cytosolic energy exchange via PCr/Cr cycling, possibly through VDACs. This effect may mask an underlying inhibition of Cr-independent ADP/ATP diffusion. This enhanced regulation of miCK-dependent phosphate shuttling may improve energy homeostasis through more efficient coupling of oxidative phosphorylation to perturbations in cellular energy charge during subsequent bouts of contraction.
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10 MeSH Terms
Progress in the function and regulation of ADP-Ribosylation.
Hottiger MO, Boothby M, Koch-Nolte F, Lüscher B, Martin NM, Plummer R, Wang ZQ, Ziegler M
(2011) Sci Signal 4: mr5
MeSH Terms: Adenosine Diphosphate, Animals, Congresses as Topic, Energy Metabolism, Enzyme Inhibitors, Humans, NAD, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Sirtuins, Switzerland
Show Abstract · Added March 20, 2014
Adenosine 5'-diphosphate (ADP)-ribosylation is a protein posttranslational modification that is catalyzed by ADP-ribosyltransferases (ARTs), using nicotinamide adenine dinucleotide (NAD(+)) as a substrate. Mono-ribosylation can be extended into polymers of ADP-ribose (PAR). Poly(ADP-ribosyl)polymerase (PARP) 1, the best-characterized cellular enzyme catalyzing this process, is the prototypical member of a family of mono- and poly(ADP-ribosyl)transferases. The physiological consequences of ADP-ribosylation are inadequately understood. PARP2010, the 18th International Conference on ADP-Ribosylation, attracted scientists from all over the world to Zurich, Switzerland. Highlights from this meeting include promising clinical trials with PARP inhibitors and new insights into cell, structural, and developmental biology of ARTs and the (glyco)hydrolase proteins that catalyze de-ADP-ribosylation of mono- or poly-ADP-ribosylated proteins. Moreover, potential links to the NAD-dependent sirtuin family were explored on the basis of a shared dependence on cellular NAD(+) concentrations and the relationship of ADP-ribosylation with intermediary metabolism and cellular energetics.
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11 MeSH Terms