Search NASA⌕ Search

SEARCH · Search NASA

Results for “HOMEOSTASIS”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Mechanism of anion exchange and small-molecule inhibition of pendrin

Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO 3 - ) exchange for chloride (Cl-) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I - ) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl - , I - , HCO 3 - or in the apo-state. The structures reveal two anion-binding sites in each protomer, and functional analyses show both sites are involved in anion exchange. The structures also show interactions between the Sulfate Transporter and Anti-Sigma factor antagonist (STAS) and transmembrane domains, and mutational studies suggest a regulatory role. We also determine the structure of pendrin in a complex with niflumic acid (NFA), which uncovers a mechanism of inhibition by competing with anion binding and impeding the structural changes necessary for anion exchange. These results reveal directions for understanding the mechanisms of anion selectivity and exchange and their regulations by the STAS domain. This work also establishes a foundation for analyzing the pathophysiology of mutations associated with Pendred syndrome.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Drosophila Evi5 is a critical regulator of intracellular iron transport via transferrin and ferritin interactions

Abstract Vesicular transport is essential for delivering cargo to intracellular destinations. Evi5 is a Rab11-GTPase-activating protein involved in endosome recycling. In humans, Evi5 is a high-risk locus for multiple sclerosis, a debilitating disease that also presents with excess iron in the CNS. In insects, the prothoracic gland (PG) requires entry of extracellular iron to synthesize steroidogenic enzyme cofactors. The mechanism of peripheral iron uptake in insect cells remains controversial. We show that Evi5-depletion in the Drosophila PG affected vesicle morphology and density, blocked endosome recycling and impaired trafficking of transferrin-1, thus disrupting heme synthesis due to reduced cellular iron concentrations. We show that ferritin delivers iron to the PG as well, and interacts physically with Evi5. Further, ferritin-injection rescued developmental delays associated with Evi5-depletion. To summarize, our findings show that Evi5 is critical for intracellular iron trafficking via transferrin-1 and ferritin, and implicate altered iron homeostasis in the etiology of multiple sclerosis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia

Abstract This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA ( n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Programmed cell death regulator BAP2 is required for IRE1-mediated unfolded protein response in Arabidopsis

Environmental and physiological situations can challenge the balance between protein synthesis and folding capacity of the endoplasmic reticulum (ER) and cause ER stress, a potentially lethal condition. The unfolded protein response (UPR) restores ER homeostasis or actuates programmed cell death (PCD) when ER stress is unresolved. The cell fate determination mechanisms of the UPR are not well understood, especially in plants. Here, we integrate genetics and ER stress profiling with natural variation and quantitative trait locus analysis of 350 natural accessions of the model species Arabidopsis thaliana . Our analyses implicate a single nucleotide polymorphism to the loss of function of the general PCD regulator BON-ASSOCIATED PROTEIN2 (BAP2) in UPR outcomes. We establish that ER stress-induced BAP2 expression is antagonistically regulated by the UPR master regulator, inositol-requiring enzyme 1 (IRE1), and that BAP2 controls adaptive UPR amplitude in ER stress and ignites pro-death mechanisms in conditions of UPR insufficiency.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

ER-associated VAP27-1 and VAP27-3 proteins functionally link the lipid-binding ORP2A at the ER-chloroplast contact sites

Abstract The plant endoplasmic reticulum (ER) contacts heterotypic membranes at membrane contact sites (MCSs) through largely undefined mechanisms. For instance, despite the well-established and essential role of the plant ER-chloroplast interactions for lipid biosynthesis, and the reported existence of physical contacts between these organelles, almost nothing is known about the ER-chloroplast MCS identity. Here we show that the Arabidopsis ER membrane-associated VAP27 proteins and the lipid-binding protein ORP2A define a functional complex at the ER-chloroplast MCSs. Specifically, through in vivo and in vitro association assays, we found that VAP27 proteins interact with the outer envelope membrane (OEM) of chloroplasts, where they bind to ORP2A. Through lipidomic analyses, we established that VAP27 proteins and ORP2A directly interact with the chloroplast OEM monogalactosyldiacylglycerol (MGDG), and we demonstrated that the loss of the VAP27-ORP2A complex is accompanied by subtle changes in the acyl composition of MGDG and PG. We also found that ORP2A interacts with phytosterols and established that the loss of the VAP27-ORP2A complex alters sterol levels in chloroplasts. We propose that, by interacting directly with OEM lipids, the VAP27-ORP2A complex defines plant-unique MCSs that bridge ER and chloroplasts and are involved in chloroplast lipid homeostasis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling

Abstract Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-β (TGF-β) family of signaling ligands. It is essential for embryonic development, tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-β isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-βs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-β bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed binding interfaces that differ from those described for the closely related co-receptor of the TGF-β family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-β signal potentiation.

Science & Technology - Other Topics↗
DOE OSTI2025

Structure and mechanism of human vesicular polyamine transporter

Polyamines play essential roles in gene expression and modulate neuronal transmission in mammals. Vesicular polyamine transporters (VPAT) from the SLC18 family exploit the transmembrane H + gradient to translocate polyamines into secretory vesicles, enabling the quantal release of polyamine neuromodulators and underpinning learning and memory formation. Here, we report the cryo-electron microscopy structures of human VPAT in complex with spermine, spermidine, H + , or tetrabenazine, elucidating discrete lumen-facing states of the antiporter and pivotal interactions between VPAT and its substrate or inhibitor. Leveraging structure-inspired mutagenesis studies and protein structure prediction, we deduce an unforeseen mechanism whereby the polyamine and H + compete for multiple acidic protein residues both directly and indirectly, and rationalize how the antidopaminergic therapeutic tetrabenazine impedes vesicular transport of polyamines. This study unravels the mechanism of an H + -coupled polyamine antiporter, reveals mechanistic diversity between VPAT and other SLC18 antiporters, and raises new prospects for combating human disorders of polyamine homeostasis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

New molecular components of high and low affinity iron import systems in Drosophila

The high abundance and molecular versatility of iron have led to its universal presence in biological systems, yet its absorption is exceptionally challenging. Animals and yeasts use divalent metal transporters to import iron, but yeasts also employ the multicopper oxidase Fet3p for high-affinity iron uptake when iron-starved. Using long-term iron depletion in Drosophila, we identified four components involved in iron absorption: Multicopper oxidase-4 (Mco4), a Fet3p ortholog, is essential for surviving iron starvation, whereas the cytochrome b561 enzymes Fire (Ferric Iron Reductase) and Fire-like, as well as cytochrome b5 protein Firewood, are required for iron absorption under normal conditions. This study reports the presence of a high-affinity iron uptake system in an animal, a cytochrome b5 electron donor for ferric iron reduction, and intestinal ferric reductases, and provides a valuable resource for further exploration of genes involved in iron homeostasis, transport, and absorption.

Iron↗
DOE OSTI2022

A soil-inspired dynamically responsive chemical system for microbial modulation

Interactions between the microbiota and their colonized environments mediate critical pathways from biogeochemical cycles to homeostasis in human health. Here, in this study, we report a soil-inspired chemical system that consists of nanostructured minerals, starch granules and liquid metals. Fabricated via a bottom-up synthesis, the soil-inspired chemical system can enable chemical redistribution and modulation of microbial communities. We characterize the composite, confirming its structural similarity to the soil, with three-dimensional X-ray fluorescence and ptychographic tomography and electron microscopy imaging. We also demonstrate that post-synthetic modifications formed by laser irradiation led to chemical heterogeneities from the atomic to the macroscopic level. The soil-inspired material possesses chemical, optical and mechanical responsiveness to yield write-erase functions in electrical performance. The composite can also enhance microbial culture/biofilm growth and biofuel production in vitro. Finally, we show that the soil-inspired system enriches gut bacteria diversity, rectifies tetracycline-induced gut microbiome dysbiosis and ameliorates dextran sulfate sodium-induced rodent colitis symptoms within in vivo rodent models.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Promiscuous G-protein activation by the calcium-sensing receptor

The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca 2+ concentration and maintains Ca 2+ homeostasis. It also mediates diverse cellular processes not associated with Ca 2+ balance. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes. Here, we determined structures of CaSR in complex with G proteins from three different subfamilies: G q , G i and G s . We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1–ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines G q and G s versus G i selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe

The inner mitochondrial membrane (IMM) generates power to drive cell function, and its dynamics control mitochondrial health and cellular homeostasis. Here, we describe the cell-permeant, lipid-like small molecule MAO-N 3 and use it to assemble high-density environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells and multiple cell states. MAO-N 3 pairs with strain-promoted azide–alkyne click chemistry-reactive fluorophores to support HIDE imaging using confocal, structured illumination, single-molecule localization and stimulated emission depletion microscopy, all with significantly improved resistance to photobleaching. These probes generate images with excellent spatial and temporal resolution, require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes (even under conditions that amplify the effects of mitochondrial toxins) and can visualize mitochondrial dynamics for 12.5 h. This probe will enable comprehensive studies of IMM dynamics with high temporal and spatial resolution.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes

Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10 –8 ) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10 –8 ) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production

Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Arabidopsis thaliana zinc accumulation in leaf trichomes is correlated with zinc concentration in leaves

Zinc (Zn) is a key micronutrient for plants and animals, and understanding Zn homeostasis in plants can improve both agriculture and human health. While root Zn transporters in plant model species have been characterized in detail, comparatively little is known about shoot processes controlling Zn concentrations and spatial distribution. Previous work showed that Zn hyperaccumulator species such as Arabidopsis halleri accumulate Zn and other metals in leaf trichomes. To date there is no systematic study regarding Zn accumulation in the trichomes of the non-accumulating, genetic model species A. thaliana. Here, we used Synchrotron X-Ray Fluorescence mapping to show that Zn accumulates at the base of trichomes of A. thaliana. Using transgenic and natural accessions of A thaliana that vary in bulk leaf Zn concentration, we demonstrate that higher leaf Zn increases total Zn found at the base of trichome cells. Our data indicates that Zn accumulation in trichomes is a function of the Zn status of the plant, and provides the basis for future studies on a genetically tractable plant species to understand the molecular steps involved in Zn spatial distribution in leaves.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Influence of intrinsic and extrinsic attributes on neonate survival in an invasive large mammal

Abstract Understanding factors influencing survival of neonates for wild species is important for successful management, particularly for determining drivers of population dynamics. Wild pigs ( Sus scrofa ) are invasive and populations are rapidly increasing in part due to high reproductive capacity. Survival of adults is generally high, however, survival of piglets, and particularly neonates, is largely unknown. We located neonates at the natal nest and quantified survival in relation to individual and maternal biological attributes, and environmental variables. During 2017–2020, we captured 50 neonates from 13 litters and documented 28 mortalities (56%) over six weeks. Survival was positively influenced by pelage coloration, likely as a form of camouflage from predators. Male neonates had higher survival. They were born larger than females, which could be beneficial for thermoregulation and competition for milk. Neonates born to larger sows had lower survival. Sow size was positively correlated with litter size, and this finding may reflect the increased nutritional demands of sustaining large litters, or difficulties in defending more neonates against predators. Neonates born in warmer months had higher survival than those born in cooler months. Neonates are inefficient thermoregulators, thus being born in warmer months could be beneficial for maintaining homeostasis as well as access to more food resources. These are the largest and most complete data for neonate wild pig survival and will inform population models for the development of management strategies to reduce negative impacts of this destructive invasive species on native ecosystems.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2023

Metal-induced oxidative stress and human plasma protein oxidation after SARS-CoV-2 infection

Pathogenesis of COVID-19 by SARS-CoV-2 resulted in a global pandemic and public health emergency in 2020. Viral infection can induce oxidative stress through reactive oxygen species (ROS). Inflammation and environmental stress are major sources of oxidative stress after infection. Micronutrients such as iron, copper, zinc, and manganese play various roles in human tissues and their imbalance in blood can impact immune responses against pathogens including SARS CoV-2. We hypothesized that alteration of free metal ions during infection and metal-catalyzed oxidation plays a critical role towards pathogenesis after infection. We analyzed convalescent and hospitalized COVID-19 patient plasma using orthogonal analytical techniques to determine redox active metal concentrations, overall protein oxidation, oxidative modifications, and protein levels via proteomics to understand the consequences of metal-induced oxidative stress in COVID-19 plasma proteins. Metal analysis using ICP-MS showed significantly greater concentrations of copper in COVID-19 plasma compared to healthy controls. We demonstrate significantly greater total protein carbonylation, other oxidative modifications, and deamidation of plasma proteins in COVID-19 plasma compared to healthy controls. Proteomics analysis showed that levels of redox active proteins including hemoglobulin were elevated in COVID-19 plasma. Molecular modeling concurred with potential interactions between iron binding proteins and SARS CoV-2 surface proteins. Overall, increased levels of redox active metals and protein oxidation indicate that oxidative stress-induced protein oxidation in COVID-19 may be a consequence of the interactions of SARS-CoV-2 proteins with host cell metal binding proteins resulting in altered cellular homeostasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Partners in root nodule symbiosis respond uniquely to heavy metal stresses in a host genotype-dependent manner

Abstract The mutualistic symbiosis between legume roots and soil rhizobia culminates in the formation of root nodules, where nitrogen is fixed. Root nodule symbiosis is inhibited by heavy metal stress. In this study, we investigated the relative responses of the symbiotic partners to a non-essential heavy metal cadmium (Cd) and an essential heavy metal zinc (Zn) stress and identified patterns in gene expression. We performed dual transcriptomics in nodules, using theMedicago truncatula-Sinorhizobium melilotisymbiotic system. Phenotypes were measured in the wild-typeMedicago truncatulaand a mutant in anABCtransporter gene (Mtabcg36), which showed compromised nodule formation in control conditions and further after heavy metal treatment. We observed that the rhizobia were particularly sensitive to Zn in mutant nodules. The greatest degree of differential gene expression in the host plant were observed under Cd and Zn treatments in wild-type nodules. Most Cd-regulated host genes were also differentially regulated by Zn, revealing little discernment between an essential and a non-essential ion under increased exposure. Furthermore, the host response to both the stresses affected auxin and iron homeostasis genes in a host genotype-dependent manner. Our results suggested impaired cadmium export from the mutant nodules. These results have potential implications in agricultural management systems and bioremediation strategies.

Science & Technology - Other Topics↗
DOE OSTI2021

Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5

Pivotal to the maintenance of cellular homeostasis, macroautophagy (hereafter autophagy) is an evolutionarily conserved degradation system that involves sequestration of cytoplasmic material into the double-membrane autophagosome and targeting of this transport vesicle to the lysosome/late endosome for degradation. EPG5 is a large-sized metazoan protein proposed to serve as a tethering factor to enforce autophagosome–lysosome/late endosome fusion specificity, and its deficiency causes a severe multisystem disorder known as Vici syndrome. Here, we show that human EPG5 (hEPG5) adopts an extended “shepherd’s staff” architecture. We find that hEPG5 binds preferentially to members of the GABARAP subfamily of human ATG8 proteins critical to autophagosome–lysosome fusion. The hEPG5–GABARAPs interaction, which is mediated by tandem LIR motifs that exhibit differential affinities, is required for hEPG5 recruitment to mitochondria during PINK1/Parkin-dependent mitophagy. Lastly, we find that the Vici syndrome mutation Gln336Arg does not affect the hEPG5’s overall stability nor its ability to engage in interaction with the GABARAPs. Collectively, results from our studies reveal new insights into how hEPG5 recognizes mature autophagosome and establish a platform for examining the molecular effects of Vici syndrome disease mutations on hEPG5.

59 BASIC BIOLOGICAL SCIENCES↗