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1.
Alzheimers Dement ; 18(2): 318-338, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34057756

RESUMO

INTRODUCTION: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. METHODS: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures. RESULTS: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation. DISCUSSION: These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy.


Assuntos
Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Demência Frontotemporal/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mitocôndrias , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 23(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36499401

RESUMO

Mesenchymal Stem Cells (MSCs) are multipotent non-hematopoietic stromal cells found in different body tissues such as bone marrow, adipose tissue, periosteum, Wharton's jelly, umbilical cord, blood, placenta, amniotic fluid, and skin. The biological behavior of MSCs depends mainly on their interaction with the microenvironment in which they are found, whose quality deeply influences the regenerative and immunomodulatory properties of these cells. Several studies confirm the interaction between MSCs and inflammatory microenvironment in the pathogenesis of psoriasis, designating MSCs as an important factor driving psoriasis development. This review aims to describe the most recent evidence on how the inflammatory microenvironment that characterizes psoriasis influences the homeostasis of MSCs and how they can be used to treat the disease.


Assuntos
Células-Tronco Mesenquimais , Geleia de Wharton , Gravidez , Feminino , Humanos , Diferenciação Celular , Cordão Umbilical , Líquido Amniótico
3.
J Neurosci ; 39(31): 6038-6048, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31147524

RESUMO

Glutamate is one of the most important neurotransmitters in the process of signal transduction in the CNS. Excessive amounts of this neurotransmitter lead to glutamate excitotoxicity, which is accountable for neuronal death in acute neurological disorders, including stroke and trauma, and in neurodegenerative diseases. Inorganic polyphosphate (PolyP) plays multiple roles in the mammalian brain, including function as a calcium-dependent gliotransmitter mediating communication between astrocytes, while its role in the regulation of neuronal activity is unknown. Here we studied the effect of PolyP on glutamate-induced calcium signal in primary rat neurons in both physiological and pathological conditions. We found that preincubation of primary neurons with PolyP reduced glutamate-induced and AMPA-induced but not the NMDA-induced calcium signal. However, in rat hippocampal acute slices, PolyP reduced ion flux through NMDA and AMPA receptors in native neurons. The effect of PolyP on glutamate and specifically on the AMPA receptors was dependent on the presence of P2Y1 but not of P2X receptor inhibitors and also could be mimicked by P2Y1 agonist 2MeSADP. Preincubation of cortical neurons with PolyP significantly reduced the initial calcium peak as well as the number of neurons with delayed calcium deregulation in response to high concentrations of glutamate and resulted in protection of neurons against glutamate-induced cell death. As a result, activation of P2Y1 receptors by PolyP reduced calcium signal acting through AMPA receptors, thus protecting neurons against glutamate excitotoxicity by reduction of the calcium overload and restoration of mitochondrial function.SIGNIFICANCE STATEMENT One of the oldest polymers in the evolution of living matter is the inorganic polyphosphate (PolyP). It is shown to play a role of gliotransmitter in the brain; however, the role of polyphosphate in neuronal signaling is not clear. Here we demonstrate that inorganic polyphosphate is able to reduce calcium signaling induced by physiological or high concentrations of glutamate. The effect of polyphosphate on glutamate-induced calcium signal in neurons is due to the effect of this polymer on the AMPA receptors. The effect of PolyP on glutamate-induced and AMPA-induced calcium signal is dependent on P2Y receptor antagonist. The ability of PolyP to restrict the glutamate-induced calcium signal lies in the basis of its protection of neurons against glutamate excitotoxicity.


Assuntos
Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Polifosfatos/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Feminino , Ácido Glutâmico/toxicidade , Masculino , Neurônios/efeitos dos fármacos , Polifosfatos/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Int J Mol Sci ; 20(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766111

RESUMO

Na+-dependent excitatory amino acid transporters (EAATs) are the major transport mechanisms for extracellular glutamate removal in the central nervous system (CNS). The primary function assigned to EAATs is the maintenance of low extracellular glutamate levels, thus allowing glutamate to be used as a signaling molecule in the brain and to avoid excitotoxicity. However, glutamate has other recognized functions. For instance, it is a key anaplerotic substrate for the tricarboxylic acid (TCA) cycle, as it can be converted to α-ketoglutarate by transaminases or glutamate dehydrogenase. Furthermore, glutamate is a precursor of the main antioxidant glutathione, which plays a pivotal role in preventing oxidative cell death. Therefore, glutamate signaling/use is at the crossroad of multiple metabolic pathways and accordingly, it can influence a plethora of cell functions, both in health and disease. Here, we provide an overview of the main functions of glutamate and its transport systems, analyzing its role as a neurotransmitter and at the same time, the possible metabolic fates it can undergo in the intracellular milieu. Specifically, the metabolic role of glutamate and the molecular machinery proposed to metabolically support its transport will be further analyzed.


Assuntos
Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Ácido Glutâmico/metabolismo , Animais , Antioxidantes/metabolismo , Sistema Nervoso Central/metabolismo , Ciclo do Ácido Cítrico , Glutationa/metabolismo , Humanos , Estresse Oxidativo , Sódio/metabolismo
5.
Stem Cells ; 34(6): 1588-600, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26891374

RESUMO

Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is a rare autosomal dominant disease caused by heterozygous mutations in the p63 gene and characterized by limb defects, orofacial clefting, ectodermal dysplasia, and ocular defects. Patients develop progressive total bilateral limbal stem cell deficiency, which eventually results in corneal blindness. Medical and surgical treatments are ineffective and of limited benefit. Oral mucosa epithelial stem cells (OMESCs) represent an alternative source of stem cells capable of regenerating the corneal epithelium and, combined with gene therapy, could provide an attractive therapeutic avenue. OMESCs from EEC patients carrying the most severe p63 mutations (p.R279H and p.R304Q) were characterized and the genetic defect of p.R279H silenced using allele-specific (AS) small interfering RNAs (siRNAs). Systematic screening of locked nucleic acid (LNA)-siRNAs against R279H-p63 allele in (i) stable WT-ΔNp63α-RFP and R279H-ΔNp63α-EGFP cell lines, (ii) transient doubly transfected cell lines, and (iii) p.R279H OMESCs, identified a number of potent siRNA inhibitors for the mutant allele, which had no effect on wild-type p63. In addition, siRNA treatment led to longer acquired life span of mutated stem cells compared to controls, less accelerated stem cell differentiation in vitro, reduced proliferation properties, and effective ability in correcting the epithelial hypoplasia, thus giving rise to full thickness stratified and differentiated epithelia. This study demonstrates the phenotypic correction of mutant stem cells (OMESCs) in EEC syndrome by means of siRNA mediated AS silencing with restoration of function. The application of siRNA, alone or in combination with cell-based therapies, offers a therapeutic strategy for corneal blindness in EEC syndrome. Stem Cells 2016;34:1588-1600.


Assuntos
Alelos , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Inativação Gênica , Mutação/genética , RNA Interferente Pequeno/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Envelhecimento/patologia , Pontos de Checagem do Ciclo Celular , Diferenciação Celular , Proliferação de Células , Autorrenovação Celular , Células Clonais , Células Epiteliais/patologia , Células HEK293 , Humanos , Limbo da Córnea/patologia , Modelos Biológicos , Mucosa Bucal/patologia , Oligonucleotídeos/metabolismo , Fenótipo , Doadores de Tecidos , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
6.
J Biomed Sci ; 24(1): 56, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28810874

RESUMO

Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital cardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope. The purpose of this review is to provide a general overview of the main genetic variants that have been linked to the major congenital cardiac channelopathies and cardiomyopathies. Functional alterations of the related proteins are also described.


Assuntos
Caveolina 3/genética , Morte Súbita Cardíaca/etiologia , Variação Genética , Cardiomiopatias/complicações , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Caveolina 3/metabolismo , Canalopatias/complicações , Canalopatias/congênito , Canalopatias/genética , Canalopatias/fisiopatologia , Humanos , Mutação
7.
J Biomed Sci ; 21: 58, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24917393

RESUMO

BACKGROUND: Sudden cardiac death (SCD) is the clinical outcome of a lethal arrhythmia that can develop on the background of unrecognized channelopathies or cardiomyopathies. Several susceptibility genes have been identified for the congenital forms of these cardiac diseases, including caveolin-3 (Cav-3) gene. In the heart Cav-3 is the main component of caveolae, plasma membrane domains that regulate multiple cellular processes highly relevant for cardiac excitability, such as trafficking, calcium homeostasis, signal transduction and cellular response to injury. Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD. RESULTS: In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells. Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress. CONCLUSION: Considering that abnormal loss of myocytes can play a mechanistic role in lethal cardiac diseases, we suggest that the detrimental effect of Cav-3 V82I variant on cell viability may participate in determining the susceptibility to cardiac death.


Assuntos
Caveolina 3 , Morte Súbita , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Mutação de Sentido Incorreto , Miócitos Cardíacos/metabolismo , Substituição de Aminoácidos , Animais , Caveolina 3/genética , Caveolina 3/metabolismo , Linhagem Celular , Cricetinae , Ativação Enzimática/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Humanos , Masculino , Miócitos Cardíacos/patologia
8.
Mol Pharmacol ; 84(4): 603-14, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23913256

RESUMO

It is known that glutamate (Glu), the major excitatory amino acid in the central nervous system, can be an essential source for cell energy metabolism. Here we investigated the role of the plasma membrane Na(+)/Ca(2+) exchanger (NCX) and the excitatory amino acid transporters (EAATs) in Glu uptake and recycling mechanisms leading to ATP synthesis. We used different cell lines, such as SH-SY5Y neuroblastoma, C6 glioma and H9c2 as neuronal, glial, and cardiac models, respectively. We first observed that Glu increased ATP production in SH-SY5Y and C6 cells. Pharmacological inhibition of either EAAT or NCX counteracted the Glu-induced ATP synthesis. Furthermore, Glu induced a plasma membrane depolarization and an intracellular Ca(2+) increase, and both responses were again abolished by EAAT and NCX blockers. In line with the hypothesis of a mutual interplay between the activities of EAAT and NCX, coimmunoprecipitation studies showed a physical interaction between them. We expanded our studies on EAAT/NCX interplay in the H9c2 cells. H9c2 expresses EAATs but lacks endogenous NCX1 expression. Glu failed to elicit any significant response in terms of ATP synthesis, cell depolarization, and Ca(2+) increase unless a functional NCX1 was introduced in H9c2 cells by stable transfection. Moreover, these responses were counteracted by EAAT and NCX blockers, as observed in SH-SY5Y and C6 cells. Collectively, these data suggest that plasma membrane EAAT and NCX are both involved in Glu-induced ATP synthesis, with NCX playing a pivotal role.


Assuntos
Trifosfato de Adenosina/biossíntese , Membrana Celular/metabolismo , Transportador 1 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/farmacologia , Trocador de Sódio e Cálcio/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Ratos
9.
Biology (Basel) ; 12(7)2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37508434

RESUMO

Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes Aß deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of Aß and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.

10.
Biochem Pharmacol ; 218: 115869, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37871878

RESUMO

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammation, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca2+ dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Gliceraldeído/metabolismo , Estresse Oxidativo , Produtos Finais de Glicação Avançada/metabolismo , Glucose/metabolismo , Peptídeos beta-Amiloides/metabolismo
11.
Antioxidants (Basel) ; 11(8)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35892658

RESUMO

Reactive oxygen species (ROS) are versatile molecules that, even if produced in the background of many biological processes and responses, possess pleiotropic roles categorized in two interactive yet opposite domains. In particular, ROS can either function as signaling molecules that shape physiological cell functions, or act as deleterious end products of unbalanced redox reactions. Indeed, cellular redox status needs to be tightly regulated to ensure proper cellular functioning, and either excessive ROS accumulation or the dysfunction of antioxidant systems can perturb the redox homeostasis, leading to supraphysiological concentrations of ROS and potentially harmful outcomes. Therefore, whether ROS would act as signaling molecules or as detrimental factors strictly relies on a dynamic equilibrium between free radical production and scavenging resources. Of notice, the mammalian brain is particularly vulnerable to ROS-mediated toxicity, because it possesses relatively poor antioxidant defenses to cope with the redox burden imposed by the elevated oxygen consumption rate and metabolic activity. Many features of neurodegenerative diseases can in fact be traced back to causes of oxidative stress, which may influence both the onset and progression of brain demise. This review focuses on the description of the dual roles of ROS as double-edge sword in both physiological and pathological settings, with reference to Alzheimer's and Parkinson's diseases.

12.
Cell Death Discov ; 8(1): 391, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127342

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder that represents the first cause of dementia. Although there has been significant progress in AD research, the actual mechanisms underlying this pathology remain largely unknown. There is increasing evidence that oxidative stress, metabolic alterations, and mitochondrial dysfunction are key players in the development and worsening of AD. As a result, in the past few years, remarkable attempts have been made to develop neuroprotective strategies against the impairment of mitochondrial dynamics and cell redox status. In the present study, we reveal a novel antioxidant K+ channel-independent effect of the M-current inhibitor XE-991 in SH-SY5Y cells differentiated with retinoic acid (RA) and primary rat cortical neurons exposed to the glycolysis inhibitor glyceraldehyde (GA). This experimental approach aimed to create a condition of hypometabolism accompanied by mitochondrial dysfunction and redox imbalance, as frequently observed in the beginning stage of the disease. We found that XE-991 exerted a neuroprotective action most likely through the resumption of superoxide dismutase (SOD) activity, which was significantly compromised during GA challenge. We also observed that the enhancement of SOD activity was accompanied by a sequence of positive effects; these included the reduction in basal Ca2+ levels within cytoplasmic and mitochondrial compartments, the decrease in mitochondrial reactive oxygen species (ROS) production, the modulation of AMPK/mTOR pathway, the recovery of ΔΨm collapse, the increase in the intracellular ATP content and the decrease in amyloid-ß (Aß) and hyperphosphorylated form of tau protein (pTau) levels. Collectively, our study reveals an off-target antioxidant effect of XE-991 and paves the way toward the further evaluation of new therapeutic uses of already existing molecules to accelerate the process of developing an effective therapy to counteract AD.

13.
Front Endocrinol (Lausanne) ; 13: 816229, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35282448

RESUMO

Background: In Cushing's syndrome (CS), chronic glucocorticoid excess (GC) and disrupted circadian rhythm lead to insulin resistance (IR), diabetes mellitus, dyslipidaemia and cardiovascular comorbidities. As undifferentiated, self-renewing progenitors of adipocytes, mesenchymal stem cells (MSCs) may display the detrimental effects of excess GC, thus revealing a promising model to study the molecular mechanisms underlying the metabolic complications of CS. Methods: MSCs isolated from the abdominal skin of healthy subjects were treated thrice daily with GCs according to two different regimens: lower, circadian-decreasing (Lower, Decreasing Exposure, LDE) versus persistently higher doses (Higher, Constant Exposure, HCE), aimed at mimicking either the physiological condition or CS, respectively. Subsequently, MSCs were stimulated with insulin and glucose thrice daily, resembling food uptake and both glucose uptake/GLUT-4 translocation and the expression of LIPE, ATGL, IL-6 and TNF-α genes were analyzed at predefined timepoints over three days. Results: LDE to GCs did not impair glucose uptake by MSCs, whereas HCE significantly decreased glucose uptake by MSCs only when prolonged. Persistent signs of IR occurred after 30 hours of HCE to GCs. Compared to LDE, MSCs experiencing HCE to GCs showed a downregulation of lipolysis-related genes in the acute period, followed by overexpression once IR was established. Conclusions: Preserving circadian GC rhythmicity is crucial to prevent the occurrence of metabolic alterations. Similar to mature adipocytes, MSCs suffer from IR and impaired lipolysis due to chronic GC excess: MSCs could represent a reliable model to track the mechanisms involved in GC-induced IR throughout cellular differentiation.


Assuntos
Síndrome de Cushing , Resistência à Insulina , Células-Tronco Mesenquimais , Síndrome de Cushing/complicações , Glucocorticoides/metabolismo , Glucose/efeitos adversos , Glucose/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Lipólise , Células-Tronco Mesenquimais/metabolismo , Erros Inatos do Metabolismo , Receptores de Glucocorticoides/deficiência
14.
Biochem Pharmacol ; 203: 115163, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35803319

RESUMO

Spatial and temporal control of calcium (Ca2+) levels is essential for the background rhythms and responses of living cells to environmental stimuli. Whatever other regulators a given cellular activity may have, localized and wider scale Ca2+ events (sparks, transients, and waves) are hierarchical determinants of fundamental processes such as cell contraction, excitability, growth, metabolism and survival. Different cell types express specific channels, pumps and exchangers to efficiently generate and adapt Ca2+ patterns to cell requirements. The Na+/Ca2+ exchangers (NCXs) in particular contribute to Ca2+ homeostasis by buffering intracellular Ca2+ loads according to the electrochemical gradients of substrate ions - i.e., Ca2+ and sodium (Na+) - and under a dynamic control of redundant regulatory processes. An interesting feature of NCX emerges from the strict relationship that connects transporter activity with cell metabolism: on the one hand NCX operates under constant control of ATP-dependent regulatory processes, on the other hand the ion fluxes generated through NCX provide mechanistic support for the Na+-driven uptake of glutamate and Ca2+ influx to fuel mitochondrial respiration. Proof of concept evidence highlights therapeutic potential of preserving a timed and balanced NCX activity in a growing rate of diseases (including excitability, neurodegenerative, and proliferative disorders) because of an improved ability of stressed cells to safely maintain ion gradients and mitochondrial bioenergetics. Here, we will summarize and review recent works that have focused on the pathophysiological roles of NCXs in balancing the two-way relationship between Ca2+ signals and metabolism.


Assuntos
Cálcio , Trocador de Sódio e Cálcio , Transporte Biológico , Cálcio/metabolismo , Homeostase/fisiologia , Sódio/metabolismo , Trocador de Sódio e Cálcio/metabolismo
15.
Pharmacol Res ; 61(4): 334-41, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19941959

RESUMO

The long-term effects of perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exposure - from gestational day (GD) 15 to postnatal day (PND) 9 - on hippocampal glutamatergic neurotransmission were studied in slices from the 40-day-old offspring of Delta(9)-THC exposed (Delta(9)-THC-rats) and vehicle-exposed (control) dams. Basal and in K+-evoked endogenous hippocampal glutamate outflow were both significantly decreased in Delta(9)-THC-rats. The effect of short Delta(9)-THC exposure (0.1microM) on K(+)-evoked glutamate release disclosed a loss of the stimulatory effect of Delta(9)-THC on hippocampal glutamate release in Delta(9)-THC-rats, but not in controls. In addition, l-[(3)H]-glutamate uptake was significantly lower in hippocampal slices from Delta(9)-THC-rats, where a significant decrease in glutamate transporter 1 (GLT1) and glutamate/aspartate transporter (GLAST) protein was also detected. Collectively, these data demonstrate that perinatal exposure to cannabinoids induces long-term impairment in hippocampal glutamatergic neurotransmission that persist into adolescence.


Assuntos
Dronabinol/toxicidade , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Feminino , Hipocampo/metabolismo , Técnicas In Vitro , Potássio/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar
16.
Cell Calcium ; 86: 102162, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31981913

RESUMO

It is well established that mitochondria are the main source of ATP production within cells. However, mitochondria have other remarkable functions, serving as important modulators of cellular Ca2+ signaling, and it is now generally recognized that control over Ca2+ homeostasis is intrinsically interwoven with mitochondrial abilities to adjust and tune ATP production. In this review, we describe the mechanisms that mitochondria use to balance Ca2+ homeostasis maintenance and cell energy metabolism. In recent years, the knowledge on the molecular machinery mediating Ca2+ influx/efflux has been improved and, albeit still open to further investigations, several lines of evidence converge on the hypothesis that plasma membrane Na+/Ca2+ exchanger (NCX) isoforms are also expressed at the mitochondrial level, where they contribute to the Ca2+ and Na+ homeostasis maintenance. In particular, the connection between mitochondrial NCX activity and metabolic substrates utilization is further discussed here. We also briefly focus on the alterations of both mitochondrial Ca2+ handling and cellular bioenergetics in neurodegenerative diseases, such as Parkinson's and Alzheimer's disease.


Assuntos
Cálcio/metabolismo , Metabolismo Energético , Homeostase , Mitocôndrias/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Animais , Sinalização do Cálcio , Humanos
17.
Cell Calcium ; 87: 102169, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32070925

RESUMO

Cell membranes spatially define gradients that drive the complexity of biological signals. To guarantee movements and exchanges of solutes between compartments, membrane transporters negotiate the passages of ions and other important molecules through lipid bilayers. The Na+/Ca2+ exchangers (NCXs) in particular play central roles in balancing Na+ and Ca2+ fluxes across diverse proteolipid borders in all eukaryotic cells, influencing cellular functions and fate by multiple means. To prevent progression from balance to disease, redundant regulatory mechanisms cooperate at multiple levels (transcriptional, translational, and post-translational) and guarantee that the activities of NCXs are finely-tuned to cell homeostatic requirements. When this regulatory network is disturbed by pathological forces, cells may approach the end of life. In this review, we will discuss the main findings, controversies and open questions about regulatory mechanisms that control NCX functions in health and disease.


Assuntos
Ativação do Canal Iônico , Trocador de Sódio e Cálcio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Humanos , Modelos Biológicos
18.
Cell Calcium ; 91: 102268, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32827867

RESUMO

Increasing evidence suggests that metabolic dysfunctions are at the roots of neurodegenerative disorders such as Alzheimer's disease (AD). In particular, defects in cerebral glucose metabolism, which have been often noted even before the occurrence of clinical symptoms and histopathological lesions, are now regarded as critical contributors to the pathogenesis of AD. Hence, the stimulation of energy metabolism, by enhancing the availability of specific metabolites, might be an alternative way to improve ATP synthesis and to positively affect AD progression. For instance, glutamate may serve as an intermediary metabolite for ATP synthesis through the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation. We have recently shown that two transporters are critical for the anaplerotic use of glutamate: the Na+-dependent Excitatory Amino Acids Carrier 1 (EAAC1) and the Na+-Ca2+ exchanger 1 (NCX1). Therefore, in the present study, we established an AD-like phenotype by perturbing glucose metabolism in both primary rat cortical neurons and retinoic acid (RA)-differentiated SH-SY5Y cells, and we explored the potential of glutamate to halt cell damage by monitoring neurotoxicity, AD markers, ATP synthesis, cytosolic Ca2+ levels and EAAC1/NCX1 functional activities. We found that glutamate significantly increased ATP production and cell survival, reduced the increase of AD biomarkers (amyloid ß protein and the hyperphosphorylated form of tau protein), and recovered the increase of NCX reverse-mode activity. The RNA silencing of either EAAC1 or NCX1 caused the loss of the beneficial effects of glutamate, suggesting the requirement of a functional interplay between these transporters for glutamate-induced protection. Remarkably, our results indicate, as proof-of-principle, that facilitating the use of alternative fuels, like glutamate, may be an effective approach to overcome deficits in glucose utilization and significantly slow down neuronal degenerative process in AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Transportador 3 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Substâncias Protetoras/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Córtex Cerebral/patologia , Gliceraldeído , Humanos , Modelos Biológicos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Tretinoína/farmacologia
19.
Cell Calcium ; 87: 102166, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32006802

RESUMO

Ionic signalling is the most ancient form of regulation of cellular functions in response to environmental challenges. Signals, mediated by Na+ fluxes and spatio-temporal fluctuations of Na+ concentration in cellular organelles and cellular compartments contribute to the most fundamental cellular processes such as membrane excitability and energy production. At the very core of ionic signalling lies the Na+-K+ ATP-driven pump (or NKA) which creates trans-plasmalemmal ion gradients that sustain ionic fluxes through ion channels and numerous Na+-dependent transporters that maintain cellular and tissue homeostasis. Here we present a brief account of the history of research into NKA, Na+ -dependent transporters and Na+ signalling.


Assuntos
Homeostase , Trocador de Sódio e Cálcio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Sódio/metabolismo , Animais , Humanos , Íons , Transdução de Sinais
20.
Cell Calcium ; 86: 102160, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31962228

RESUMO

Energy metabolism impairment is a central event in the pathophysiology of ischemia. The limited availability of glucose and oxygen strongly affects mitochondrial activity, thus leading to ATP depletion. In this setting, the switch to alternative energy sources could ameliorate cells survival by enhancing ATP production, thus representing an attractive strategy for ischemic treatment. In this regard, some studies have recently re-evaluated the metabolic role of glutamate and its potential to promote cell survival under pathological conditions. In the present review, we discuss the ability of glutamate to exert an "energizing role" in cardiac and neuronal models of hypoxia/reoxygenation (H/R) injury, focusing on the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino acid transporters (EAATs) as key players in this metabolic pathway.


Assuntos
Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Ácido Glutâmico/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Sobrevivência Celular , Metabolismo Energético , Humanos
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