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One of the major events of early plant immune responses is a rapid influx of Ca2+ into the cytosol following pathogen recognition. Indeed, changes in cytosolic Ca2+ are recognized as ubiquitous elements of cellular signaling networks and are thought to encode stimulus-specific information in their duration, amplitude, and frequency. Despite the wealth of observations showing that the bacterial elicitor peptide flg22 triggers Ca2+ transients, there remain limited data defining the molecular identities of Ca2+ transporters involved in shaping the cellular Ca2+ dynamics during the triggering of the defense response network. However, the autoinhibited Ca2+-ATPase (ACA) pumps that act to expel Ca2+ from the cytosol have been linked to these events, with knockouts in the vacuolar members of this family showing hypersensitive lesion-mimic phenotypes. We have therefore explored how the two tonoplast-localized pumps, ACA4 and ACA11, impact flg22-dependent Ca2+ signaling and related defense responses. The double-knockout aca4/11 exhibited increased basal Ca2+ levels and Ca2+ signals of higher amplitude than wild-type plants. Both the aberrant Ca2+ dynamics and associated defense-related phenotypes could be suppressed by growing the aca4/11 seedlings at elevated temperatures. Relocalization of ACA8 from its normal cellular locale of the plasma membrane to the tonoplast also suppressed the aca4/11 phenotypes but not when a catalytically inactive mutant was used. These observations indicate that regulation of vacuolar Ca2+ sequestration is an integral component of plant immune signaling, but also that the action of tonoplastlocalized Ca2+ pumps does not require specific regulatory elements not found in plasma membrane-localized pumps.

Calcium is used in many cellular processes and is maintained within the cell as free calcium at low concentrations (approximately 100 nM), compared with extracellular (millimolar) concentrations, to avoid adverse effects such as phosphate precipitation. For this reason, cells have adapted buffering strategies by compartmentalizing calcium into mitochondria and the endoplasmic reticulum (ER). In mitochondria, the calcium concentration is in the millimolar range, as it is in the ER. Mitochondria actively contribute to buffering cellular calcium, but if matrix calcium increases beyond physiological demands, it can promote the opening of the mitochondrial permeability transition pore (mPTP) and, consequently, trigger apoptotic or necrotic cell death. The pathophysiological implications of mPTP opening in ischemia-reperfusion, liver, muscle, and lysosomal storage diseases, as well as those affecting the central nervous system, for example, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have been reported. In this review, we present an updated overview of the main cellular mechanisms of mitochondrial calcium regulation. We specially focus on neurodegenerative diseases related to imbalances in calcium homeostasis and summarize some proposed therapies studied to attenuate these diseases.

Astrocytic Ca 2+ signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. However, the anatomical basis of such specific signaling remains unclear, owing to difficulties in resolving the spongiform domain of astrocytes where most tripartite synapses are located. Using 3D-STED microscopy in living organotypic brain slices, we imaged the spongiform domain of astrocytes and observed a reticular meshwork of nodes and shafts that often formed loop-like structures. These anatomical features were also observed in acute hippocampal slices and in barrel cortex in vivo. The majority of dendritic spines were contacted by nodes and their sizes were correlated. FRAP experiments and Ca 2+ imaging showed that nodes were biochemical compartments and Ca 2+ microdomains. Mapping astrocytic Ca 2+ signals onto STED images of nodes and dendritic spines showed they were associated with individual synapses. Here, we report on the nanoscale organization of astrocytes, identifying nodes as a functional astrocytic component of tripartite synapses that may enable synapse-specific communication between neurons and astrocytes. Astrocytic Ca 2+ signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. Here, the authors report the organization of astrocytes at nanoscale level and identify nodes as a functional astrocytic component of tripartite synapses.

The dangerous chemical hydrogen fluoride sits at the apex of the fluorochemical industry, but the substantial hazards linked to its production under harsh conditions (above 300 degrees Celsius) and transport are typically contracted to specialists. All fluorochemicals for applications, including refrigeration, electric transportation, agrochemicals and pharmaceuticals, are prepared from fluorspar (CaF 2 ) through a procedure that generates highly dangerous hydrogen fluoride 1 – 5 . Here we report a mild method to obtain fluorochemicals directly from fluorspar, bypassing the necessity to manufacture hydrogen fluoride. Acid-grade fluorspar (more than 97 per cent CaF 2 ) is treated with the fluorophilic Lewis acid boric acid (B(OH) 3 ) or silicon dioxide (SiO 2 ), in the presence of oxalic acid, a Brønsted acid that is highly effective for Ca 2+ sequestration. This scalable process carried out in water at low temperature (below 50 degrees Celsius) enables access to widely used fluorochemicals, including tetrafluoroboric acid, alkali metal fluorides, tetraalkylammonium fluorides and fluoro(hetero)arenes. The replacement of oxalic acid with sulfuric acid gave comparable results for B(OH) 3 , but was not as effective when the fluorophilic Lewis acid was SiO 2 . A similar process also works with the lower-purity metspar. The production of fluorochemicals directly from fluorspar offers the possibility of decentralized manufacturing—an attractive model for the fluorochemical industry. With the renewed interest in innovative methods to synthesize oxalic acid via carbon dioxide capture and biomass 6 , 7 , and the challenges posed by our dependence on fossil fuels for sulfur and therefore sulfuric acid supply 8 , 9 , our technology may represent a departure towards a sustainable fluorochemical industry. Fluorochemicals are obtained directly from fluorspar activated in water at low temperature, without the requirement to manufacture hydrogen fluoride, a toxic and hazardous gas that is central to the current industrial process.

It is extremely challenging to quantitate lumenal Ca2+ in acidic Ca2+ stores of the cell because all Ca2+ indicators are pH sensitive, and Ca2+ transport is coupled to pH in acidic organelles. We have developed a fluorescent DNA-based reporter, CalipHluor, that is targetable to specific organelles. By ratiometrically reporting lumenal pH and Ca2+ simultaneously, CalipHluor functions as a pH-correctable Ca2+ reporter. By targeting CalipHluor to the endolysosomal pathway, we mapped lumenal Ca2+ changes during endosomal maturation and found a surge in lumenal Ca2+ specifically in lysosomes. Using lysosomal proteomics and genetic analysis, we found that catp-6, a Caenorhabditis elegans homolog of ATP13A2, was responsible for lysosomal Ca2+ accumulation—an example of a lysosome-specific Ca2+ importer in animals. By enabling the facile quantification of compartmentalized Ca2+, CalipHluor can expand the understanding of subcellular Ca2+ importers.

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus . Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy. Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.

Mast cells and basophils are main drivers of allergic reactions and anaphylaxis, for which prevalence is rapidly increasing. Activation of these cells leads to a tightly controlled release of inflammatory mediators stored in secretory granules. The release of these granules is dependent on intracellular calcium (Ca2+) signals. Ca2+ release from endolysosomal compartments is mediated via intracellular cation channels, such as two-pore channel (TPC) proteins. Here, we uncover a mechanism for how TPC1 regulates Ca2+ homeostasis and exocytosis in mast cells in vivo and ex vivo. Notably, in vivo TPC1 deficiency in mice leads to enhanced passive systemic anaphylaxis, reflected by increased drop in body temperature, most likely due to accelerated histamine-induced vasodilation. Ex vivo, mast cell-mediated histamine release and degranulation was augmented upon TPC1 inhibition, although mast cell numbers and size were diminished. Our results indicate an essential role of TPC1 in endolysosomal Ca2+ uptake and filling of endoplasmic reticulum Ca2+ stores, thereby regulating exocytosis in mast cells. Thus, pharmacological modulation of TPC1 might blaze a trail to develop new drugs against mast cell-related diseases, including allergic hypersensitivity.

Greenhouse gas emissions and climate change concerns have prompted worldwide initiatives to lower carbon dioxide (CO2) levels and prevent them from rising in the atmosphere, thereby controlling global warming. Effective CO2 management through carbon capture and storage is essential for safe and permanent storage, as well as synchronically meeting carbon reduction targets. Lowering CO2 emissions through carbon utilization can develop a wide range of new businesses for energy security, material production, and sustainability. CO2 mineralization is one of the most promising strategies for producing thermodynamically stable solid calcium or magnesium carbonates for long-term sequestration using simple chemical reactions. Current advancements in CO2 mineralization technologies,focusing on pathways and mechanisms using different industrial solid wastes, including natural minerals as feedstocks, are briefly discussed. However, the operating costs, energy consumption, reaction rates, and material management are major barriers to the application of these technologies in CO2 mineralization. The optimization of operating parameters, tailor-made equipment, and smooth supply of waste feedstocks require more attention to make the carbon mineralization process economically and commercially viable. Here, carbonation mechanisms, technological options to expedite mineral carbonation, environmental impacts, and prospects of CO2 mineralization technologies are critically evaluated to suggest a pathway for mitigating climate change in the future. The integration of industrial wastes and brine with the CO2 mineralization process can unlock its potential for the development of novel chemical pathways for the synthesis of calcium or magnesium carbonates, valuable metal recovery, and contribution to sustainability goals while reducing the impact of global warming.

The endoplasmic reticulum (ER) is the major intracellular calcium (Ca 2+ ) storage compartment in eukaryotic cells. In most instances, the mobilization of Ca 2+ from this store is followed by a delayed and sustained uptake of Ca 2+ through Ca 2+ -permeable channels of the cell surface named store-operated Ca 2+ channels (SOCCs). This gives rise to a store-operated Ca 2+ entry (SOCE) that has been thoroughly investigated in electrically non-excitable cells where it is the principal regulated Ca 2+ entry pathway. The existence of this Ca 2+ route in neurons has long been a matter of debate. However, a growing body of experimental evidence indicates that the recruitment of Ca 2+ from neuronal ER Ca 2+ stores generates a SOCE. The present review summarizes the main studies supporting the presence of a depletion-dependent Ca 2+ entry in neurons. It also addresses the question of the molecular composition of neuronal SOCCs, their expression, pharmacological properties, as well as their physiological relevance.

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP₃R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP₃R activation and a dramatic shortening of Drosophila life-span. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP₃Rs. Manipulations that either lowered PLC-β/IP₃R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP₃R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.