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1.
Mitochondrial dysfunction as a critical event in the pathophysiology of bipolar disorder.
Scaini, G, Andrews, T, Lima, CNC, Benevenuto, D, Streck, EL, Quevedo, J
Mitochondrion. 2021;:23-36
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Abstract
The understanding of the pathophysiology of bipolar disorder (BD) remains modest, despite recent advances in neurobiological research. The mitochondrial dysfunction hypothesis of bipolar disorder has been corroborated by several studies involving postmortem brain analysis, neuroimaging, and specific biomarkers in both rodent models and humans. Evidence suggests that BD might be related to abnormal mitochondrial morphology and dynamics, neuroimmune dysfunction, and atypical mitochondrial metabolism and oxidative stress pathways. Mitochondrial dysfunction in mood disorders is also associated with abnormal Ca2+ levels, glutamate excitotoxicity, an imbalance between pro- and antiapoptotic proteins towards apoptosis, abnormal gene expression of electron transport chain complexes, and decreased ATP synthesis. This paper aims to review and discuss the implications of mitochondrial dysfunction in BD etiology and to explore mitochondria as a potential target for novel therapeutic agents.
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Perisynaptic astrocytes as a potential target for novel antidepressant drugs.
Frizzo, ME, Ohno, Y
Journal of pharmacological sciences. 2021;(1):60-68
Abstract
Emerging evidence suggests that dysfunctions in glutamatergic signaling are associated with the pathophysiology of depression. Several molecules that act on glutamate binding sites, so-called glutamatergic modulators, are rapid-acting antidepressants that stimulate synaptogenesis. Their antidepressant response involves the elevation of both extracellular glutamate and brain-derived neurotrophic factor (BDNF) levels, as well as the postsynaptic activation of the mammalian target of rapamycin complex 1. The mechanisms involved in the antidepressant outcomes of glutamatergic modulators, including ketamine, suggest that astrocytes must be considered a cellular target for developing rapid-acting antidepressants. It is well known that extracellular glutamate levels and glutamate intrasynaptic time-coursing are maintained by perisynaptic astrocytes, where inwardly rectifying potassium channels 4.1 (Kir4.1 channels) regulate both potassium and glutamate uptake. In addition, ketamine reduces membrane expression of Kir4.1 channels, which raises extracellular potassium and glutamate levels, increasing postsynaptic neural activities. Furthermore, inhibition of Kir4.1 channels stimulates BDNF expression in astrocytes, which may enhance synaptic connectivity. In this review, we discuss glutamatergic modulators' actions in regulating extracellular glutamate and BDNF levels, and reinforce the importance of perisynaptic astrocytes for the development of novel antidepressant drugs.
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Dietary glutamic acid and aspartic acid as biomarkers for predicting diabetic retinopathy.
Park, SY, Kim, J, Son, JI, Rhee, SY, Kim, DY, Chon, S, Lim, H, Woo, JT
Scientific reports. 2021;(1):7244
Abstract
The screening rate of diabetic retinopathy (DR) is low despite the importance of early diagnosis. We investigated the predictive value of dietary glutamic acid and aspartic acid for diagnosis of DR using the Korea National Diabetes Program cohort study. The 2067 patients with type 2 diabetes without DR were included. The baseline intakes of energy, glutamic acid and aspartic acid were assessed using a 3-day food records. The risk of DR incidence based on intake of glutamic acid and aspartic acid was analyzed. The DR group was older, and had higher HbA1c, longer DM duration, lower education level and income than non-DR group (all p < 0.05). The intake of total energy, glutamic acid and aspartic acid were lower in DR group than non-DR group (p = 0.010, p = 0.025 and p = 0.042, respectively). There was no difference in the risk of developing DR according to the intake of glutamic acid and ascorbic acid. But, aspartic acid intake had a negative correlation with PDR. Hence, the intake of glutamic acid and aspartic acid did not affect in DR incidence. However, lower aspartic acid intake affected the PDR incidence.
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Unveiling a key role of oxaloacetate-glutamate interaction in regulation of respiration and ROS generation in nonsynaptic brain mitochondria using a kinetic model.
Selivanov, VA, Zagubnaya, OA, Nartsissov, YR, Cascante, M
PloS one. 2021;(8):e0255164
Abstract
Glutamate plays diverse roles in neuronal cells, affecting cell energetics and reactive oxygen species (ROS) generation. These roles are especially vital for neuronal cells, which deal with high amounts of glutamate as a neurotransmitter. Our analysis explored neuronal glutamate implication in cellular energy metabolism and ROS generation, using a kinetic model that simulates electron transport details in respiratory complexes, linked ROS generation and metabolic reactions. The analysis focused on the fact that glutamate attenuates complex II inhibition by oxaloacetate, stimulating the latter's transformation into aspartate. Such a mechanism of complex II activation by glutamate could cause almost complete reduction of ubiquinone and deficiency of oxidized form (Q), which closes the main stream of electron transport and opens a way to massive ROS generating transfer in complex III from semiquinone radicals to molecular oxygen. In this way, under low workload, glutamate triggers the respiratory chain (RC) into a different steady state characterized by high ROS generation rate. The observed stepwise dependence of ROS generation on glutamate concentration experimentally validated this prediction. However, glutamate's attenuation of oxaloacetate's inhibition accelerates electron transport under high workload. Glutamate-oxaloacetate interaction in complex II regulation underlies the observed effects of uncouplers and inhibitors and acceleration of Ca2+ uptake. Thus, this theoretical analysis uncovered the previously unknown roles of oxaloacetate as a regulator of ROS generation and glutamate as a modifier of this regulation. The model predicted that this mechanism of complex II activation by glutamate might be operative in situ and responsible for excitotoxicity. Spatial-time gradients of synthesized hydrogen peroxide concentration, calculated in the reaction-diffusion model with convection under a non-uniform local approximation of nervous tissue, have shown that overproduction of H2O2 in a cell causes excess of its level in neighbor cells.
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Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study.
Lehn-Stefan, A, Peter, A, Machann, J, Schick, F, Randrianarisoa, E, Heni, M, Wagner, R, Birkenfeld, AL, Fritsche, A, Häring, HU, et al
The Journal of clinical endocrinology and metabolism. 2021;(2):e982-e989
Abstract
OBJECTIVE Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis. METHODS Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT). RESULTS Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ -.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05). CONCLUSIONS Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
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Novel Glutamate-Putrescine Ligase Activity in Haloferax mediterranei: A New Function for glnA-2 Gene.
Rodríguez-Herrero, V, Peris, A, Camacho, M, Bautista, V, Esclapez, J, Bonete, MJ
Biomolecules. 2021;(8)
Abstract
The genome of the halophilic archaea Haloferax mediterranei contains three ORFs that show homology with glutamine synthetase (GS) (glnA-1, glnA-2, and glnA-3). Previous studies have focused on the role of GlnA-1, suggesting that proteins GlnA-2 and GlnA-3 could play a different role to that of GS. Glutamine synthetase (EC 6.3.1.2) belongs to the class of ligases, including 20 subclasses of other different enzymes, such as aspartate-ammonia ligase (EC 6.3.1.1), glutamate-ethylamine ligase (EC 6.3.1.6), and glutamate-putrescine ligase (EC 6.3.1.11). The reaction catalyzed by glutamate-putrescine ligase is comparable to the reaction catalyzed by glutamine synthetase (GS). Both enzymes can bind a glutamate molecule to an amino group: ammonium (GS) or putrescine (glutamate-putrescine ligase). In addition, they present the characteristic catalytic domain of GS, showing significant similarities in their structure. Although these proteins are annotated as GS, the bioinformatics and experimental results obtained in this work indicate that the GlnA-2 protein (HFX_1688) is a glutamate-putrescine ligase, involved in polyamine catabolism. The most significant results are those related to glutamate-putrescine ligase's activity and the analysis of the transcriptional and translational expression of the glnA-2 gene in the presence of different nitrogen sources. This work confirms a new metabolic pathway in the Archaea domain which extends the knowledge regarding the utilization of alternative nitrogen sources in this domain.
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7.
Possibility that the Onset of Autism Spectrum Disorder is Induced by Failure of the Glutamine-Glutamate Cycle.
Kawada, K, Kuramoto, N, Mimori, S
Current molecular pharmacology. 2021;(2):170-174
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors. In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine- glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.
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8.
Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.
Younis, S, Christensen, CE, Vestergaard, MB, Lindberg, U, Tolnai, D, Paulson, OB, Larsson, HB, Hougaard, A, Ashina, M
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021;(3):604-616
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Abstract
Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
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Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis.
Nilsson, A, Haanstra, JR, Engqvist, M, Gerding, A, Bakker, BM, Klingmüller, U, Teusink, B, Nielsen, J
Proceedings of the National Academy of Sciences of the United States of America. 2020;(19):10294-10304
Abstract
Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets.
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Platelet glutamate uptake and Th1 cells inversely correlate in relapsing/remitting and in progressive multiple sclerosis.
M, G, G, DC, M, F, M, R, M, C, C, B, S, A, G, C, R, F, C, F, et al
Multiple sclerosis and related disorders. 2020;:102007
Abstract
BACKGROUND High affinity sodium-dependent Excitatory Amino Acid Transporters (EAAT), present in glial and neuron cells, clear around 90% of the synaptic cleft released glutamate, and their impaired activity seem to be critical for many neurodegenerative disorders, including Multiple Sclerosis (MS). These transporters are also present in human platelets, and they show molecular and biochemical characteristics similar to those in the CNS. OBJECTIVES The aim of this study was to investigate whether EAAT-dependent uptake is present also at the peripheral level in blood of MS patients. Moreover, since platelets (plt) and peripheral blood mononuclear cells (PBMC) share the same intra-corporeal fluid, they might be reciprocally influenced, and the glutamate uptake modulation might be useful as a peripheral "trait-marker" to characterize different clinical courses of MS RESULTS : Reduced uptake values were found in MS patients compared to healthy controls (HC), as well as significant differences were found across MS clinical courses. Representative saturation curves showed that Vmax was significantly decreased for patients compared to HC. Conversely, dissociation constant of the two reactions appeared similar for MS and HC subjects. Furthermore, clinical forms of MS with mild (benign) prognosis was not affected as fa as concern EAAT uptake. Gender, age, and drug treatments did not impact glutamate uptake efficiency. Interestingly, a negative correlation between EAAT activity and percentage of Th1 cells (CD4+IFNγ+ and CD4+TBET+IFNγ+ cells) was observed, suggesting a relationship between EAAT impairment and a pro-inflammatory environment. CONCLUSIONS Interestingly, as shown in the CNS, a relationship between clinical, inflammatory MS features and glutamate clearance can be also assessed in platelets. Moreover, glutamate uptake activity might be an useful biomarker to characterize patients with benign prognosis.