Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function

Fidler, Trevor P.; Campbell, Robert A.; Funari, Trevor; Dunne, Nicholas; Angeles, Enrique Balderas; Middleton, Elizabeth; Chaudhuri, Dipayan; Weyrch, Andrew S.; Abel, E. Dale

doi:10.1016/j.celrep.2017.06.083

Cited by 60 publications

(31 citation statements)

References 33 publications

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“…AIF1v1, on the other hand, seems to be involved in glucose metabolism and platelet activation suggesting a role in platelet glycolysis, but there is no data in the literature regarding this particular isoform. Glucose metabolism plays a critical role in the production, activation, and survival of platelets according to a recent study [ 40 ] and relationships between tumor and the hemostatic system is being recognized as an important BC regulator [ 41 ]. Considering these results, the potential roles and characterization of AIF1 were further explored.…”

Section: Resultsmentioning

confidence: 99%

An isoform of AIF1 involved in breast cancer

et al. 2018

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BackgroundInflammation is a major player in breast cancer (BC) progression. Allograft-inflammatory factor-1 (AIF1) is a crucial mediator in the inflammatory response. AIF1 reportedly plays a role in BC, but the mechanism remains to be elucidated. We identified two AIF1 isoforms, AIF1v1 and AIF1v3, which were differentially expressed between affected and unaffected sisters from families with high risk of BC with no deleterious BRCA1/BRCA2 mutations (BRCAX). We investigated potential functions of AIFv1/v3 in BC of varying severity and breast adipose tissue by evaluating their expression, and association with metabolic and clinical parameters of BC patients.MethodsAIF1v1/v3 expression was determined in BC tissues and cell lines using quantitative real-time PCR. Potential roles and mechanisms were examined in the microenvironment (fibroblasts, adipose tissue, monocytes and macrophages), inflammatory response (cell reaction in BC subgroups), and metabolism [treatment with docosahexaenoic acid (DHA)]. Association of AIF1 transcript expression with clinical factors was determined by Spearman’s rank correlation. Bioinformatics analyses were performed to characterize transcripts.ResultsAIF1v1/v3 were mostly expressed in the less severe BC samples, and their expression appeared to originate from the tumor microenvironment. AIF1 isoforms had different expression rates and sources in breast adipose tissue; lymphocytes mostly expressed AIF1v1 while activated macrophages mainly expressed AIF1v3. Bioinformatics analysis revealed major structural differences suggesting distinct functions in BC progression. Lymphocytes were the most infiltrating cells in breast tumors and their number correlated with AIF1v1 adipose expression. Furthermore, DHA supplementation significantly lowered the expression of AIF1 isoforms in BRCAX cell lines. Finally, the expression of AIF1 isoforms in BC and breast adipose tissue correlated with clinical parameters of BC patients.ConclusionsResults strongly suggest that AIF1v1 as much as AIF1v3 play a major role in the crosstalk between BC and infiltrating immune cells mediating tumor progression, implying their high potential as target molecules for BC diagnostic, prognostication and treatment.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0663-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

An isoform of AIF1 involved in breast cancer

et al. 2018

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“…Recently, Fidler and coworkers demonstrated that SOD2-KO platelets showed increased mitochondrial ROS; however, total platelet ROS content remained unchanged. Furthermore, deletion of SOD2 did not alter tail-bleeding or arterial thrombosis in vivo, suggesting that SOD2 is dispensable for platelet redox balance [ 81 , 82 ].…”

Section: Endogenous and Exogenous Antioxidant Systems As Regulatormentioning

confidence: 99%

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Masselli

Pozzi

Vaccarezza

et al. 2020

IJMS

136

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Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers.

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“… 21 − 28 GLUT3 is also expressed in lymphocytes, monocytes, macrophages, and platelets where it is stored in the intracellular vesicles and, when needed for an increase in glucose demand, it can be translocated and fused to the plasma membrane upon cellular activation. 6 , 29 In the structural studies of GLUTs that are resolved to atomistic resolutions only recently, multiple crystal structures of GLUT3 have been determined, 30 all in the outward-open/occluded (exofacial) conformations but none inward-open/occluded (endofacial). Interestingly, multiple crystal structures of GLUT1 are currently available in the endofacial conformations 31 , 32 but none exofacial.…”

Section: Introductionmentioning

confidence: 99%

Gibbs Free-Energy Gradient along the Path of Glucose Transport through Human Glucose Transporter 3

Liang

Bourdon

Chen

et al. 2018

ACS Chem. Neurosci.

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Fourteen glucose transporters (GLUTs) play essential roles in human physiology by facilitating glucose diffusion across the cell membrane. Due to its central role in the energy metabolism of the central nervous system, GLUT3 has been thoroughly investigated. However, the Gibbs free-energy gradient (what drives the facilitated diffusion of glucose) has not been mapped out along the transport path. Some fundamental questions remain. Here we present a molecular dynamics study of GLUT3 embedded in a lipid bilayer to quantify the free-energy profile along the entire transport path of attracting a β-d-glucose from the interstitium to the inside of GLUT3 and, from there, releasing it to the cytoplasm by Arrhenius thermal activation. From the free-energy profile, we elucidate the unique Michaelis–Menten characteristics of GLUT3, low KM and high VMAX, specifically suitable for neurons’ high and constant demand of energy from their low-glucose environments. We compute GLUT3’s binding free energy for β-d-glucose to be −4.6 kcal/mol in agreement with the experimental value of −4.4 kcal/mol (KM = 1.4 mM). We also compute the hydration energy of β-d-glucose, −18.0 kcal/mol vs the experimental data, −17.8 kcal/mol. In this, we establish a dynamics-based connection from GLUT3’s crystal structure to its cellular thermodynamics with quantitative accuracy. We predict equal Arrhenius barriers for glucose uptake and efflux through GLUT3 to be tested in future experiments.

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Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function

Cited by 60 publications

References 33 publications

An isoform of AIF1 involved in breast cancer

An isoform of AIF1 involved in breast cancer

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Gibbs Free-Energy Gradient along the Path of Glucose Transport through Human Glucose Transporter 3

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