Content uploaded by Feng-Yen Li
Author content
All content in this area was uploaded by Feng-Yen Li
Content may be subject to copyright.
A preview of the PDF is not available
Second messenger role for Mg2+ revealed by human T-cell immunodeficiency
Abstract and Figures
The magnesium ion, Mg(2+), is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca(2+) does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg(2+) influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg(2+) influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase Cγ1 and a markedly impaired Ca(2+) influx in T cells but not B cells. These observations reveal a role for Mg(2+) as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics.
Figures - uploaded by Feng-Yen Li
Author content
All figure content in this area was uploaded by Feng-Yen Li
Content may be subject to copyright.
... Ligandinduced mobilization of the remaining unbound free i Mg 2+ can control several cellular functions. 1,[4][5][6][7][8][9] Intracellular ion mobilization is tightly regulated through organelle-specific ion channels and transporters. Since 1974, several findings alluded that i Mg 2+ has a second messenger role. ...
... Since 1974, several findings alluded that i Mg 2+ has a second messenger role. 4,7,[10][11][12] The proposition of i Mg 2+ as a dynamic second messenger raises an important fundamental question: How do Mg 2+ transporters facilitate rapid Mg 2+ influx when the intra-and extracellular [Mg 2+ ] are nearly comparable? Recently, we revealed that the glycolytic end-product lactate induces rapid depletion of endoplasmic reticulum (ER) Mg 2+ stores, followed by robust mitochondrial Mg 2+ ( m Mg 2+ ) uptake. ...
... Magnesium (Mg) is an essential element for bone health and diseases because it is involved in the physiological processes of bone tissue formation, bone metabolism and bone mineral crystallisation 35,36 . In humans, approximately 60% of Mg is stored in the bone matrix 37 . ...
The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Various biomaterials have been developed to enhance bone regeneration, but the limitations on the shape-adaptive capacity, the complexity of clinical operation, and the unsatisfied osteogenic bioactivity have greatly restricted their clinical application. In this work, we construct a mechanically robust, tailorable and water-responsive shape-memory silk fibroin/magnesium (SF/MgO) composite scaffold, which is able to quickly match irregular defects by simple trimming, thus leading to good interface integration. We demonstrate that the SF/MgO scaffold exhibits excellent mechanical stability and structure retention during the degradative process with the potential for supporting ability in defective areas. This scaffold further promotes the proliferation, adhesion and migration of osteoblasts and the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. With suitable MgO content, the scaffold exhibits good histocompatibility, low foreign-body reactions (FBRs), significant ectopic mineralisation and angiogenesis. Skull defect experiments on male rats demonstrate that the cell-free SF/MgO scaffold markedly enhances bone regeneration of cranial defects. Taken together, the mechanically robust, personalised and bioactive scaffold with water-responsive shape-memory may be a promising biomaterial for clinical-size and irregular bone defect regeneration.
... In the progression of OA, the balance between cartilage and bone formation and resorption is mainly influenced by three cell types, including bone marrow mesenchymal stem cells (BMSCs), chondrocytes, and osteoclasts (22). As a ubiquitous element found in almost all cell types, Mg 2+ has been shown to effectively stabilize enzymes and nucleic acids, thereby exerting therapeutic effects on various cells in OA (23). Thus, Mg 2+ may attenuate OA by acting on various cell types, but the precise therapeutic mechanism of Mg 2+ remains obscure. ...
The emerging therapeutic strategies for osteoarthritis (OA) are shifting toward comprehensive approaches that target periarticular tissues, involving both cartilage and subchondral bone. This shift drives the development of single-component therapeutics capable of acting on multiple tissues and cells. Magnesium, an element essential for maintaining skeletal health, shows promise in treating OA. However, the precise effects of magnesium on cartilage and subchondral bone are not yet clear. Here, we investigated the therapeutic effect of Mg ²⁺ on OA, unveiling its protective effects on both cartilage and bone at the cellular and animal levels. The beneficial effect on the cartilage-bone interaction is primarily mediated by the PI3K/AKT pathway. In addition, we developed poly(lactic- co -glycolic acid) (PLGA) microspheres loaded with nano-magnesium oxide modified with stearic acid (SA), MgO&SA@PLGA, for intra-articular injection. These microspheres demonstrated remarkable efficacy in alleviating OA in rat models, highlighting their translational potential in clinical applications.
... Additionally, Mg is essential for maintaining the stability of DNA and RNA, the genetic material in our cells, and it also plays a role in cell growth and specialization. More than 600 enzymes in our bodies rely on Mg to function properly, and there are around 200 other enzymes where Mg helps activate their activities (Rubin, 2005;Kubota et al., 2005;Iotti et al., 2005;Feeney et al., 2016;Li et al., 2011;Fiorentini et al., 2021;Sargenti et al., 2018;Mammoli et al., 2019;Caspi et al., 2020). ...
Metal oxide nanoparticles, such as MgO nanoparticles (NPs), possess various beneficial properties like antibacterial, antiviral, antifungal, and antibiofilm effects. However, traditional chemical synthesis methods for producing MgO NPs have two issues: poor biocompatibility and the formation of harmful substances that can harm the environment. To address these concerns, there has been a growing interest in eco-friendly techniques, employing greener chemistry to produce nanoparticles through alternative routes. Four distinct approaches are used by plants, fungi, bacteria, and algae to generate MgO nanoparticles. These methods utilize the metabolites produced by biological materials and their extracts to stabilize and cap the particles, leading to nanoparticle formation. Factors like pH, extraction ratio, and temperature significantly impact the size, stability, shape, and surface area of the resulting MgO nanoparticles. The use of green methods or biomethods to synthesize nanoparticles offers several advantages, such as being eco-friendly and nontoxic to living organisms, making them well-suited for various biological applications. The synthesized MgO nanoparticles have demonstrated promising potential as effective agents against pathogens, particularly in biomedical fields, due to their biocompatibility and eco-friendliness. Their antibacterial properties primarily result from the disruption of cell walls or membranes and the generation of reactive oxygen species (ROS). However, there remain gaps in our understanding of the long-term toxicity, diffusion, absorption, and excretion mechanisms of these nanoparticles. To further explore their potential uses, additional research is required, either in laboratory settings (in vitro) or within living organisms (in vivo). By genetically modifying plant sources, it becomes feasible to control the configuration, uniformity, and resilience of the nanoparticles. Conducting thorough assessments of the antioxidant potential of biogenic MgO NPs will provide valuable insights into their practical applications. In conclusion, eco-friendly synthesis methods for MgO nanoparticles hold great promise for industrial and biological uses. Their inherent biocompatibility and environmentally friendly nature make them valuable candidates for a wide range of applications, especially in combating pathogens. However, further research is necessary to fully realize their potential benefits and explore their contributions to societal betterment.
Magnesium is an essential ion in the human body that regulates numerous physiological and pathological processes. Magnesium deficiency is very common in old age. Age-related chronic diseases and the aging process itself are frequently associated with low-grade chronic inflammation, called ‘inflammaging’. Because chronic magnesium insufficiency has been linked to excessive generation of inflammatory markers and free radicals, inducing a chronic inflammatory state, we formerly hypothesized that magnesium inadequacy may be considered among the intermediaries helping us explain the link between inflammaging and aging-associated diseases. We show in this review evidence of the relationship of magnesium with all the hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled autophagy, dysbiosis, and chronic inflammation), which may positively affect the human healthspan. It is feasible to hypothesize that maintaining an optimal balance of magnesium during one’s life course may turn out to be a safe and economical strategy contributing to the promotion of healthy aging. Future well-designed studies are necessary to further explore this hypothesis.
Human SCID (Severe Combined Immunodeficiency) is a prenatal disorder of T lymphocyte development, that depends on the expression of numerous genes. The knowledge of the genetic basis of SCID is essential for diagnosis (e.g., clinical phenotype, lymphocyte profile) and treatment (e.g., use and type of pre-hematopoietic stem cell transplant conditioning).
Over the last years novel genetic defects causing SCID have been discovered, and the molecular and immunological mechanisms of SCID have been better characterized. Distinct forms of SCID show both common and peculiar (e.g., absence or presence of nonimmunological features) aspects, and they are currently classified into six groups according to prevalent pathophysiological mechanisms: impaired cytokine-mediated signaling; pre-T cell receptor defects; increased lymphocyte apoptosis; defects in thymus embryogenesis; impaired calcium flux; other mechanisms.
This review is the updated, extended and largely modified translation of the article "Cossu F: Le basi genetiche delle SCID", originally published in Italian language in the journal "Prospettive in Pediatria" 2009, 156:228-238.
X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecule-associated protein (SAP; encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP; encoded by BIRC4) is mutated in XLP2. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation. To date, XLP2 has been found to cause HLH with and without exposure to Epstein-Barr virus, and HLH is commonly recurrent in these patients. For both forms of XLP, the only curative therapy at present is allogeneic hematopoietic cell transplantation. Beyond their common X-linked locus and their requirement for normal immune responses to certain viral infections, SAP and XIAP demonstrate no obvious structural or functional similarity, are not coordinately regulated with respect to their expression, and do not appear to directly interact. In this review, we describe the genetic, clinical, and immunopathologic features of these 2 disorders and discuss current diagnostic and therapeutic strategies.
Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders.
Detailed clinical assessment, electrophysiological studies, survey of the literature.
In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy.
A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques--such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities.
Phospholipase Cgamma1 (PLCgamma1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCgamma1 in T cell biology, we generated and examined mice with T cell-specific deletion of PLCgamma1. We demonstrate that PLCgamma1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-kappaB. Importantly, PLCgamma1 deficiency impairs the development and function of FoxP3(+) regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCgamma1 is essential for T cell development, activation, and tolerance.
DNA and a large proportion of RNA are antiparallel duplexes composed of an unvarying phosphosugar backbone surrounding uniformly stacked and highly similar base pairs. How do the myriad of enzymes (including ribozymes) that perform catalysis on nucleic acids achieve exquisite structure or sequence specificity? In all DNA and RNA polymerases and many nucleases and transposases, two Mg2+ ions are jointly coordinated by the nucleic acid substrate and catalytic residues of the enzyme. Based on the exquisite sensitivity of Mg2+ ions to the ligand geometry and electrostatic environment, we propose that two-metal-ion catalysis greatly enhances substrate recognition and catalytic specificity.
Calcium functions as a secondary messenger within the cytosols of eukaryotes. This serves as a reference point to evaluate three related questions:1.Calcium, as well as cyclic AMP, also functions as a paracrine messenger; how specific and extensive is this use?2.Calcium binding proteins and calcium extrusion mechanisms have been identified in prokaryotes; does it function as a messenger?3.The concentrations of other divalent cations, especially zinc and magnesium, are well regulated and perturbations have specific physiological impacts; are these divalents involved in information transfer?Exploration of these three interrelated questions indicates the importance of more sensitive techniques and of a refined concept of information transfer and transduction.
Phospholipase C-gamma1 (PLC-gamma1), a tyrosine kinase substrate, has been implicated in the pathway for the epidermal growth factor receptor (EGFR)-induced cell migration. However, the underlying mechanism by which PLC-gamma1 mediates EGFR-induced cell migration remains elusive. In the present study, we sought to determine whether the lipase activity of PLC-gamma1 is required for EGFR-induced cell migration. We found that overexpression of PLC-gamma1 in squamous cell carcinoma SCC4 cells markedly enhanced EGF-induced PLC-gamma1 activation, intracellular calcium rise, and cell migration. This enhancement was abolished by mutational inactivation of the catalytic domain of PLC-gamma1. Inhibition of the downstream signaling processes mediated by the activity of phospholipase C (PLC) using IP(3) receptor inhibitor or intracellular calcium chelator blocked EGF-induced cell migration. These data indicate that EGF-induced cell migration is mediated by the lipase domain of PLC-gamma1 and the subsequent IP(3) generation and intracellular calcium mobilization.
Ca(2+) entry into cells of the peripheral immune system occurs through highly Ca(2+)-selective channels known as CRAC (calcium release-activated calcium) channels. CRAC channels are a very well-characterized example of store-operated Ca(2+) channels, so designated because they open when the endoplasmic reticulum (ER) Ca(2+) store becomes depleted. Physiologically, Ca(2+) is released from the ER lumen into the cytoplasm when activated receptors couple to phospholipase C and trigger production of the second messenger inositol 1,4,5-trisphosphate (IP(3)). IP(3) binds to IP(3) receptors in the ER membrane and activates Ca(2+) release. The proteins STIM and ORAI were discovered through limited and genome-wide RNAi screens, respectively, performed in Drosophila cells and focused on identifying modulators of store-operated Ca(2+) entry. STIM1 and STIM2 sense the depletion of ER Ca(2+) stores, whereas ORAI1 is a pore subunit of the CRAC channel. In this review, we discuss selected aspects of Ca(2+) signaling in cells of the immune system, focusing on the roles of STIM and ORAI proteins in store-operated Ca(2+) entry.