Publications by authors named "Alessio Menga"

24 Publications

  • Page 1 of 1

Cachexia, a Systemic Disease beyond Muscle Atrophy.

Int J Mol Sci 2020 Nov 14;21(22). Epub 2020 Nov 14.

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy.

Cachexia is a complication of dismal prognosis, which often represents the last step of several chronic diseases. For this reason, the comprehension of the molecular drivers of such a condition is crucial for the development of management approaches. Importantly, cachexia is a syndrome affecting various organs, which often results in systemic complications. To date, the majority of the research on cachexia has been focused on skeletal muscle, muscle atrophy being a pivotal cause of weight loss and the major feature associated with the steep reduction in quality of life. Nevertheless, defining the impact of cachexia on other organs is essential to properly comprehend the complexity of such a condition and potentially develop novel therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21228592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696729PMC
November 2020

Editorial: Metabolism Meets Function: Untangling the Cross-Talk Between Signaling and Metabolism.

Front Oncol 2020 20;10:607511. Epub 2020 Oct 20.

Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Torino, Torino, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.607511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607004PMC
October 2020

Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages.

EMBO Mol Med 2020 10 4;12(10):e11210. Epub 2020 Sep 4.

Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.

Glutamine synthetase (GS) generates glutamine from glutamate and controls the release of inflammatory mediators. In macrophages, GS activity, driven by IL10, associates to the acquisition of M2-like functions. Conditional deletion of GS in macrophages inhibits metastasis by boosting the formation of anti-tumor, M1-like, tumor-associated macrophages (TAMs). From this basis, we evaluated the pharmacological potential of GS inhibitors in targeting metastasis, identifying glufosinate as a specific human GS inhibitor. Glufosinate was tested in both cultured macrophages and on mice bearing metastatic lung, skin and breast cancer. We found that glufosinate rewires macrophages toward an M1-like phenotype both at the primary tumor and metastatic site, countering immunosuppression and promoting vessel sprouting. This was also accompanied to a reduction in cancer cell intravasation and extravasation, leading to synchronous and metachronous metastasis growth inhibition, but no effects on primary tumor growth. Glufosinate treatment was well-tolerated, without liver and brain toxicity, nor hematopoietic defects. These results identify GS as a druggable enzyme to rewire macrophage functions and highlight the potential of targeting metabolic checkpoints in macrophages to treat cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/emmm.201911210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539200PMC
October 2020

Understanding Metal Dynamics Between Cancer Cells and Macrophages: Competition or Synergism?

Front Oncol 2020 30;10:646. Epub 2020 Apr 30.

Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.

Metal ions, such as selenium, copper, zinc, and iron are naturally present in the environment (air, drinking water, and food) and are vital for cellular functions at chemical, molecular, and biological levels. These trace elements are involved in various biochemical reactions by acting as cofactors for many enzymes and control important biological processes by binding to the receptors and transcription factors. Moreover, they are essential for the stabilization of the cellular structures and for the maintenance of genome stability. A body of preclinical and clinical evidence indicates that dysregulation of metal homeostasis, both at intracellular and tissue level, contributes to the pathogenesis of many different types of cancer. These trace minerals play a crucial role in preventing or accelerating neoplastic cell transformation and in modulating the inflammatory and pro-tumorigenic response in immune cells, such as macrophages, by controlling a plethora of metabolic reactions. In this context, macrophages and cancer cells interact in different manners and some of these interactions are modulated by availability of metals. The current review discusses the new findings and focuses on the involvement of these micronutrients in metabolic and cellular signaling mechanisms that influence macrophage functions, onset of cancer and its progression. An improved understanding of "metallic" cross-talk between macrophages and cancer cells may pave the way for innovative pharmaceutical or dietary interventions in order to restore the balance of these trace elements and also strengthen the chemotherapeutic treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203474PMC
April 2020

Pharmacological targets of metabolism in disease: Opportunities from macrophages.

Pharmacol Ther 2020 06 6;210:107521. Epub 2020 Mar 6.

Department of Biomedical Sciences, University of Padua, Italy; Fondazione Città della Speranza, Istituto di Ricerca Pediatrica, Padua, Italy. Electronic address:

From advances in the knowledge of the immune system, it is emerging that the specialized functions displayed by macrophages during the course of an immune response are supported by specific and dynamically-connected metabolic programs. The study of immunometabolism is demonstrating that metabolic adaptations play a critical role in modulating inflammation and, conversely, inflammation deeply influences the acquisition of specific metabolic settings.This strict connection has been proven to be crucial for the execution of defined immune functional programs and it is now under investigation with respect to several human disorders, such as diabetes, sepsis, cancer, and autoimmunity. The abnormal remodelling of the metabolic pathways in macrophages is now emerging as both marker of disease and potential target of therapeutic intervention. By focusing on key pathological conditions, namely obesity and diabetes, rheumatoid arthritis, atherosclerosis and cancer, we will review the metabolic targets suitable for therapeutic intervention in macrophages. In addition, we will discuss the major obstacles and challenges related to the development of therapeutic strategies for a pharmacological targeting of macrophage's metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2020.107521DOI Listing
June 2020

Impact of Immunometabolism on Cancer Metastasis: A Focus on T Cells and Macrophages.

Cold Spring Harb Perspect Med 2020 09 1;10(9). Epub 2020 Sep 1.

Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium.

Despite improved treatment options, cancer remains the leading cause of morbidity and mortality worldwide, with 90% of this mortality correlated to the development of metastasis. Since metastasis has such an impact on treatment success, disease outcome, and global health, it is important to understand the different steps and factors playing key roles in this process, how these factors relate to immune cell function and how we can target metabolic processes at different steps of metastasis in order to improve cancer treatment and patient prognosis. Recent insights in immunometabolism direct to promising therapeutic targets for cancer treatment, however, the specific contribution of metabolism on antitumor immunity in different metastatic niches warrant further investigation. Here, we provide an overview of what is so far known in the field of immunometabolism at different steps of the metastatic cascade, and what may represent the next steps forward. Focusing on metabolic checkpoints in order to translate these findings from in vitro and mouse studies to the clinic has the potential to revolutionize cancer immunotherapy and greatly improve patient prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/cshperspect.a037044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461771PMC
September 2020

The Crowded Crosstalk between Cancer Cells and Stromal Microenvironment in Gynecological Malignancies: Biological Pathways and Therapeutic Implication.

Int J Mol Sci 2019 May 15;20(10). Epub 2019 May 15.

Department of Biomedical and Human Oncological Science, 2nd Unit of Obstetrics and Gynecology, University of Bari "Aldo Moro", Piazza G. Cesare, 11-Policlinico 70124 Bari, Italy.

The tumor microenvironment plays a pillar role in the progression and the distance dissemination of cancer cells in the main malignancies affecting women-epithelial ovarian cancer, endometrial cancer and cervical cancer. Their acquires specific properties thanks to intense crosstalk between stromal and cancer cells, leading to a vicious circle. Fibroblasts, pericytes, lymphocytes and tumor associated-macrophages orchestrate most of the biological pathways. In epithelial ovarian cancer, high rates of activated pericytes determine a poorer prognosis, defining a common signature promoting ovarian cancer proliferation, local invasion and distant spread. Mesenchymal cells also release chemokines and cytokines under hormonal influence, such as estrogens that drive most of the endometrial cancers. Interestingly, the architecture of the cervical cancer is shaped by the synergy of high-risk Human Papilloma Virus oncoproteins and the activity of stromal estrogen receptor α. Lymphocytes represent a shield against cancer cells but some cell subpopulation could lead to immunosuppression, tumor growth and dissemination. Cytotoxic tumor infiltrating lymphocytes can be eluded by over-adapted cancer cells in a scenario of immune-tolerance driven by T-regulatory cells. Therefore, the tumor microenvironment has a high translational potential offering many targets for biological and immunological therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20102401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567055PMC
May 2019

FOXD3 acts as a repressor of the mitochondrial S-adenosylmethionine carrier (SLC25A26) gene expression in cancer cells.

Biochimie 2018 Nov 2;154:25-34. Epub 2018 Aug 2.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125, Bari, Italy. Electronic address:

The mitochondrial S-adenosylmethionine carrier (SAMC), encoded by the SLC25A26 gene, catalyzes the uptake of S-adenosylmethionine (SAM) from the cytosol into mitochondria in exchange for S-adenosylhomocysteine (SAH), produced inside the mitochondria. In the last years we have been functionally characterizing the promoter of SLC25A26 gene. In this study we show that a silencer activity is present in the region from -756 bp to -504 bp, which specifically binds a protein present in Caski cells nuclear extracts. By in silico analysis, EMSA, ChIP, overexpressing and silencing experiments this protein was identified as FOXD3 which acts as a repressor of SLC25A26 expression. Interestingly, the repressor activity of FOXD3 is completely abolished by treating Caski cells with folate via a mechanism that involves methylation of FOXD3 gene promoter. This finding could have important impact in cancer cells where SLC25A26 is downregulated. Finally, the DPE and INR putative sites were also identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2018.07.025DOI Listing
November 2018

Monoamine oxidase-dependent histamine catabolism accounts for post-ischemic cardiac redox imbalance and injury.

Biochim Biophys Acta Mol Basis Dis 2018 09 25;1864(9 Pt B):3050-3059. Epub 2018 Jun 25.

Department of Biomedical Sciences, University of Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Padova, Italy. Electronic address:

Monoamine oxidase (MAO), a mitochondrial enzyme that oxidizes biogenic amines generating hydrogen peroxide, is a major source of oxidative stress in cardiac injury. However, the molecular mechanisms underlying its overactivation in pathological conditions are still poorly characterized. Here, we investigated whether the enhanced MAO-dependent hydrogen peroxide production can be due to increased substrate availability using a metabolomic profiling method. We identified N-methylhistamine -the main catabolite of histamine- as an important substrate fueling MAO in Langendorff mouse hearts, directly perfused with a buffer containing hydrogen peroxide or subjected to ischemia/reperfusion protocol. Indeed, when these hearts were pretreated with the MAO inhibitor pargyline we observed N-methylhistamine accumulation along with reduced oxidative stress. Next, we showed that synaptic terminals are the major source of N-methylhistamine. Indeed, in vivo sympathectomy caused a decrease of N-methylhistamine levels, which was associated with a marked protection in post-ischemic reperfused hearts. As far as the mechanism is concerned, we demonstrate that exogenous histamine is transported into isolated cardiomyocytes and triggers a rise in the levels of reactive oxygen species (ROS). Once again, pargyline pretreatment induced intracellular accumulation of N-methylhistamine along with decrease in ROS levels. These findings uncover a receptor-independent mechanism for histamine in cardiomyocytes. In summary, our study reveals a novel and important pathophysiological causative link between MAO activation and histamine availability during pathophysiological conditions such as oxidative stress/cardiac injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2018.06.018DOI Listing
September 2018

Glutamine Synthetase: Localization Dictates Outcome.

Genes (Basel) 2018 Feb 19;9(2). Epub 2018 Feb 19.

Hematology Unit, National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II', Bari 70124, Italy.

Glutamine synthetase (GS) is the adenosine triphosphate (ATP)-dependent enzyme that catalyses the synthesis of glutamine by condensing ammonium to glutamate. In the circulatory system, glutamine carries ammonia from muscle and brain to the kidney and liver. In brain reduction of GS activity has been suggested as a mechanism mediating neurotoxicity in neurodegenerative disorders. In cancer, the delicate balance between glutamine synthesis and catabolism is a critical event. In vitro evidence, confirmed in vivo in some cases, suggests that reduced GS activity in cancer cells associates with a more invasive and aggressive phenotype. However, GS is known to be highly expressed in cells of the tumor microenvironment, such as fibroblasts, adipocytes and immune cells, and their ability to synthesize glutamine is responsible for the acquisition of protumoral phenotypes. This has opened a new window into the complex scenario of the tumor microenvironment, in which the balance of glutamine consumption versus glutamine synthesis influences cellular function. Since GS expression responds to glutamine starvation, a lower glutamine synthesizing power due to the absence of GS in cancer cells might apply a metabolic pressure on stromal cells. This event might push stroma towards a GS-high/protumoral phenotype. When referred to stromal cells, GS expression might acquire a 'bad' significance to the point that GS inhibition might be considered a conceivable strategy against cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes9020108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852604PMC
February 2018

SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency.

Hum Mol Genet 2018 02;27(3):499-504

Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70125 Bari, Italy.

Mitochondrial diseases are a plethora of inherited neuromuscular disorders sharing defects in mitochondrial respiration, but largely different from one another for genetic basis and pathogenic mechanism. Whole exome sequencing was performed in a familiar trio (trio-WES) with a child affected by severe epileptic encephalopathy associated with respiratory complex I deficiency and mitochondrial DNA depletion in skeletal muscle. By trio-WES we identified biallelic mutations in SLC25A10, a nuclear gene encoding a member of the mitochondrial carrier family. Genetic and functional analyses conducted on patient fibroblasts showed that SLC25A10 mutations are associated with reduction in RNA quantity and aberrant RNA splicing, and to absence of SLC25A10 protein and its transporting function. The yeast SLC25A10 ortholog knockout strain showed defects in mitochondrial respiration and mitochondrial DNA content, similarly to what observed in the patient skeletal muscle, and growth susceptibility to oxidative stress. Albeit patient fibroblasts were depleted in the main antioxidant molecules NADPH and glutathione, transport assays demonstrated that SLC25A10 is unable to transport glutathione. Here, we report the first recessive mutations of SLC25A10 associated to an inherited severe mitochondrial neurodegenerative disorder. We propose that SLC25A10 loss-of-function causes pathological disarrangements in respiratory-demanding conditions and oxidative stress vulnerability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddx419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886107PMC
February 2018

Metabolism and TAM functions-it takes two to tango.

FEBS J 2018 02 8;285(4):700-716. Epub 2017 Nov 8.

Hematology Unit, National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.

From the evidence on clinical studies and experimental mouse models we now know that tumor-associated macrophages (TAMs) sustain tumor development in many different ways. They play a role in angiogenesis, tumor cell invasion, and metastasis formation. Additionally, TAMs interfere with natural killer and T-cell antitumoral activities, producing an immune-suppressive environment that protects tumor cell growth. This indicates that the tumoricidal activity of macrophages within the tumor microenviroment is lost due to an imbalance of the regulatory mechanisms underpinning these cells' function. Since metabolism is emerging as a major modulator of macrophage function, metabolic changes in response to signals coming from cancer or other immune cells might promote this imbalance, enhancing the tumorigenic activities of TAMs. In this review we describe the novel, most recent findings on how metabolism shapes TAM functions or conversely, how TAMs influence the activity of other cells through metabolic mechanisms. The complete elucidation of the metabolic switches between pro- and antitumoral properties of macrophages, now still in its infancy, is destined to provide scientists with new instruments not only to understand but also to combat cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.14295DOI Listing
February 2018

Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis.

Cell Rep 2017 08;20(7):1654-1666

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; Hematology Unit, National Cancer Research Center, Istituto Tumori "Giovanni Paolo II," 70124 Bari, Italy. Electronic address:

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.07.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575233PMC
August 2017

SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism.

FEBS J 2017 03 21;284(6):967-984. Epub 2017 Feb 21.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy.

Cancer cells down-regulate different genes to give them a selective advantage in invasiveness and/or metastasis. The SLC25A26 gene encodes the mitochondrial carrier that catalyzes the import of S-adenosylmethionine (SAM) into the mitochondrial matrix, required for mitochondrial methylation processes, and is down-regulated in cervical cancer cells. In this study we show that SLC25A26 is down-regulated due to gene promoter hypermethylation, as a mechanism to promote cell survival and proliferation. Furthermore, overexpression of SLC25A26 in CaSki cells increases mitochondrial SAM availability and promotes hypermethylation of mitochondrial DNA, leading to decreased expression of key respiratory complex subunits, reduction of mitochondrial ATP and release of cytochrome c. In addition, increased SAM transport into mitochondria leads to impairment of the methionine cycle with accumulation of homocysteine at the expense of glutathione, which is strongly reduced. All these events concur to arrest the cell cycle in the S phase, induce apoptosis and enhance chemosensitivity of SAM carrier-overexpressing CaSki cells to cisplatin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.14028DOI Listing
March 2017

The contribution of the citrate pathway to oxidative stress in Down syndrome.

Immunology 2016 Dec 3;149(4):423-431. Epub 2016 Oct 3.

Department of Science, University of Basilicata, Potenza, Italy.

Inflammatory conditions and oxidative stress have a crucial role in Down syndrome (DS). Emerging studies have also reported an altered lipid profile in the early stages of DS. Our previous works demonstrate that citrate pathway activation is required for oxygen radical production during inflammation. Here, we find up-regulation of the citrate pathway and down-regulation of carnitine/acylcarnitine carrier and carnitine palmitoyl-transferase 1 genes in cells from children with DS. Interestingly, when the citrate pathway is inhibited, we observe a reduction in oxygen radicals as well as in lipid peroxidation levels. Our preliminary findings provide evidence for a citrate pathway dysregulation, which could be related to some phenotypic traits of people with DS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.12659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095497PMC
December 2016

Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells.

Antioxid Redox Signal 2017 03 2;26(8):351-363. Epub 2016 Nov 2.

1 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari , Bari, Italy .

Aims: Microglial cells are brain-resident macrophages engaged in surveillance and maintained in a constant state of relative inactivity. However, their involvement in autoimmune diseases indicates that in pathological conditions microglia gain an inflammatory phenotype. The mechanisms underlying this change in the microglial phenotype are still unclear. Since metabolism is an important modulator of immune cell function, we focused our attention on glutamine synthetase (GS), a modulator of the response to lipopolysaccharide (LPS) activation in other cell types, which is expressed by microglia.

Results: GS inhibition enhances release of inflammatory mediators of LPS-activated microglia in vitro, leading to perturbation of the redox balance and decreased viability of cocultured neurons. GS inhibition also decreases insulin-mediated glucose uptake in microglia. In vivo, microglia-specific GS ablation enhances expression of inflammatory markers upon LPS treatment. In the spinal cords from experimental autoimmune encephalomyelitis (EAE), GS expression levels and glutamine/glutamate ratios are reduced.

Innovation: Recently, metabolism has been highlighted as mediator of immune cell function through the discovery of mechanisms that (behind these metabolic changes) modulate the inflammatory response. The present study shows for the first time a metabolic mechanism mediating microglial response to a proinflammatory stimulus, pointing to GS activity as a master modulator of immune cell function and thus unraveling a potential therapeutic target.

Conclusions: Our study highlights a new role of GS in modulating immune response in microglia, providing insights into the pathogenic mechanisms associated with inflammation and new strategies of therapeutic intervention. Antioxid. Redox Signal. 26, 351-363.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2016.6715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346956PMC
March 2017

Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines.

Biol Chem 2017 03;398(3):303-317

Significant metabolic changes occur in the shift from resting to activated cellular status in inflammation. Thus, changes in expression of a large number of genes and extensive metabolic reprogramming gives rise to acquisition of new functions (e.g. production of cytokines, intermediates for biosynthesis, lipid mediators, PGE, ROS and NO). In this context, mitochondrial carriers, which catalyse the transport of solute across mitochondrial membrane, change their expression to transport mitochondrially produced molecules, among which citrate and succinate, to be used as intracellular signalling molecules in inflammation. This review summarises the mitochondrial carriers studied so far that are, directly or indirectly, involved in inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/hsz-2016-0260DOI Listing
March 2017

Acetylation of human mitochondrial citrate carrier modulates mitochondrial citrate/malate exchange activity to sustain NADPH production during macrophage activation.

Biochim Biophys Acta 2015 Aug 24;1847(8):729-38. Epub 2015 Apr 24.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", Bari, Italy; Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

The mitochondrial citrate-malate exchanger (CIC), a known target of acetylation, is up-regulated in activated immune cells and plays a key role in the production of inflammatory mediators. However, the role of acetylation in CIC activity is elusive. We show that CIC is acetylated in activated primary human macrophages and U937 cells and the level of acetylation is higher in glucose-deprived compared to normal glucose medium. Acetylation enhances CIC transport activity, leading to a higher citrate efflux from mitochondria in exchange with malate. Cytosolic citrate levels do not increase upon activation of cells grown in deprived compared to normal glucose media, indicating that citrate, transported from mitochondria at higher rates from acetylated CIC, is consumed at higher rates. Malate levels in the cytosol are lower in activated cells grown in glucose-deprived compared to normal glucose medium, indicating that this TCA intermediate is rapidly recycled back into the cytosol where it is used by the malic enzyme. Additionally, in activated cells CIC inhibition increases the NADP+/NADPH ratio in glucose-deprived cells; this ratio is unchanged in glucose-rich grown cells due to the activity of the pentose phosphate pathway. Consistently, the NADPH-producing isocitrate dehydrogenase level is higher in activated glucose-deprived as compared to glucose rich cells. These results demonstrate that, in the absence of glucose, activated macrophages increase CIC acetylation to enhance citrate efflux from mitochondria not only to produce inflammatory mediators but also to meet the NADPH demand through the actions of isocitrate dehydrogenase and malic enzyme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbabio.2015.04.009DOI Listing
August 2015

Elements in support of the 'non-identity' of the PGRMC1 protein with the σ2 receptor.

Eur J Pharmacol 2015 Jul 3;758:16-23. Epub 2015 Apr 3.

Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy.

σ2 Receptor subtype is overexpressed in a variety of human tumors, with σ2 agonists showing antiproliferative effects towards tumor cells through multiple pathways that depend both on the tumor cell type and on the molecule type. Therefore, σ2 receptor is an intriguing target for tumor diagnosis and treatment despite the fact that that it has not yet been cloned. One of the last attempts to characterize σ2 receptors led to identify it as the progesterone receptor membrane component 1 (PGRMC1). Although still controversial, such identity appears to have been accepted. We the aim of contributing to solve this controversy, in this work we stably silenced or overexpressed PGRMC1 protein in human MCF7 adenocarcinoma cells. Western blotting analyses were performed to quantify the presence of PGRMC1 protein on each of the three MCF7 cell lines variants, while scatchard analyses with radioligand were performed in order to determine the expression of the σ2 receptors. In order to correlate the antiproliferative effect of σ2 receptor agonist with PGRMC1 density, some σ2 ligands were administered to each of the three MCF7 cells variants. The results suggested that PGRMC1 and σ2 receptors are two different molecular entities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2015.03.067DOI Listing
July 2015

The mitochondrial aspartate/glutamate carrier isoform 1 gene expression is regulated by CREB in neuronal cells.

Int J Biochem Cell Biol 2015 Mar 14;60:157-66. Epub 2015 Jan 14.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy. Electronic address:

The aspartate/glutamate carrier isoform 1 is an essential mitochondrial transporter that exchanges intramitochondrial aspartate and cytosolic glutamate across the inner mitochondrial membrane. It is expressed in brain, heart and muscle and is involved in important biological processes, including myelination. However, the signals that regulate the expression of this transporter are still largely unknown. In this study we first identify a CREB binding site within the aspartate/glutamate carrier gene promoter that acts as a strong enhancer element in neuronal SH-SY5Y cells. This element is regulated by active, phosphorylated CREB protein and by signal pathways that modify the activity of CREB itself and, most noticeably, by intracellular Ca(2+) levels. Specifically, aspartate/glutamate carrier gene expression is induced via CREB by forskolin while it is inhibited by the PKA inhibitor, H89. Furthermore, the CREB-induced activation of gene expression is increased by thapsigargin, which enhances cytosolic Ca(2+), while it is inhibited by BAPTA-AM that reduces cytosolic Ca(2+) or by STO-609, which inhibits CaMK-IV phosphorylation. We further show that CREB-dependent regulation of aspartate/glutamate carrier gene expression occurs in neuronal cells in response to pathological (inflammation) and physiological (differentiation) conditions. Since this carrier is necessary for neuronal functions and is involved in myelinogenesis, our results highlight that targeting of CREB activity and Ca(2+) might be therapeutically exploited to increase aspartate/glutamate carrier gene expression in neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biocel.2015.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344217PMC
March 2015

Glutamine synthetase desensitizes differentiated adipocytes to proinflammatory stimuli by raising intracellular glutamine levels.

FEBS Lett 2014 Dec 20;588(24):4807-14. Epub 2014 Nov 20.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy. Electronic address:

The role of glutamine synthetase (GS) during adipocyte differentiation is unclear. Here, we assess the impact of GS on the adipocytic response to a proinflammatory challenge at different differentiation stages. GS expression at the late stages of differentiation desensitized mature adipocytes to bacterial lipopolysaccharide (LPS) by increasing intracellular glutamine levels. Furthermore, LPS-activated mature adipocytes were unable to produce inflammatory mediators; LPS sensitivity was rescued following GS inhibition and the associated drop in intracellular glutamine levels. The ability of adipocytes to differentially respond to LPS during differentiation negatively correlates to GS expression and intracellular glutamine levels. Hence, modulation of intracellular glutamine levels by GS expression represents an endogenous mechanism through which mature adipocytes control the inflammatory response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.febslet.2014.11.015DOI Listing
December 2014

A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation.

Biochim Biophys Acta 2014 Nov 27;1839(11):1217-1225. Epub 2014 Jul 27.

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona 4, 70125 Bari, Italy.

The chronic induction of inflammation underlies multiple pathological conditions, including metabolic, autoimmune disorders and cancer. The mitochondrial citrate carrier (CIC), encoded by the SLC25A1 gene, promotes the export of citrate from the mitochondria to the cytoplasm, a process that profoundly influences energy balance in the cells. We have previously shown that SLC25A1 is a target gene for lipopolysaccharide signaling and promotes the production of inflammatory mediators. We now demonstrate that SLC25A1 is induced at the transcriptional level by two key pro-inflammatory cytokines, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ), and such induction involves the activity of the nuclear factor kappa B and STAT1 transcription factors. By studying the down-stream events following SLC25A1 activation during signals that mimic inflammation, we demonstrate that CIC is required for regulating the levels of nitric oxide and of prostaglandins by TNFα or IFNγ. Importantly, we show that the citrate exported from mitochondria via CIC and its downstream metabolic intermediate, acetyl-coenzyme A, are necessary for TNFα or IFNγ to induce nitric oxide and prostaglandin production. These findings provide the first line of evidence that the citrate export pathway, via CIC, is central for cytokine-induced inflammatory signals and shed new light on the relationship between energy metabolism and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagrm.2014.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346166PMC
November 2014

ATP-citrate lyase is essential for macrophage inflammatory response.

Biochem Biophys Res Commun 2013 Oct 17;440(1):105-11. Epub 2013 Sep 17.

Department of Science, University of Basilicata, 85100 Potenza, Italy. Electronic address:

Growing evidence suggests that energy metabolism and inflammation are closely linked and that cross-talk between these processes is fundamental to the pathogenesis of many human diseases. However, the molecular mechanisms underlying these observations are still poorly understood. Here we describe the key role of ATP-citrate lyase (ACLY) in inflammation. We find that ACLY mRNA and protein levels markedly and quickly increase in activated macrophages. Importantly, ACLY activity inhibition as well as ACLY gene silencing lead to reduced nitric oxide, reactive oxygen species and prostaglandin E2 inflammatory mediators. In conclusion, we present a direct role for ACLY in macrophage inflammatory metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2013.09.037DOI Listing
October 2013

MEF2C exon α: role in gene activation and differentiation.

Gene 2013 Dec 2;531(2):355-62. Epub 2013 Sep 2.

Department of Science, University of Basilicata, 85100 Potenza, Italy. Electronic address:

Myocyte enhancer factor 2C (MEF2C) belongs to the MEF2 transcription factors. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain. All four vertebrate MEF2 gene transcripts are also alternatively spliced. In the present study we identify two novel MEF2C splice variants, named VP and VP2. These variants are generated by the skipping of exon α. The identified α- variants are ubiquitously expressed, although at very low levels compared to the α+ variants. The existence of MEF2C α- variants gave us the opportunity to study for the first time the function of exon α. Transactivation experiments show that the presence of exon α induces a reduction of transcription levels. Moreover, α- variants are significantly expressed during neuronal cell differentiation, indicating a putative role of these variants in development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2013.08.044DOI Listing
December 2013