Energy Metabolites Research Articles

Mechanistic effects of lipid binding pockets within soluble signaling proteins: Lessons from acyl-CoA-binding and START-domain-containing proteins.

While lipids serve as important energy reserves, metabolites, and cellular constituents in all forms of life, these macromolecules also function as unique carriers of information in plant communication given their diverse chemical structures. The signal transduction process involves a sophisticated interplay between messengers, receptors, signal transducers, and downstream effectors. Over the years, an array of plant signaling proteins have been identified for their crucial roles in perceiving lipid signals. However, the mechanistic effects of lipid binding on protein functions remain largely elusive. Recent literature has presented numerous fascinating models that illustrate the significance of protein-lipid interactions in mediating signaling responses. This review focuses on the category of lipophilic signaling proteins that encompass a hydrophobic binding pocket located outside of cellular membranes and provides an update on the lessons learned from two of these structures, namely the acyl-CoA-binding and START domains. It begins with a brief overview of the latest advances in understanding the functions of the two protein families in plant communication. The second part highlights five functional mechanisms of lipid ligands in concert with their target signaling proteins.

Mixed Th1/Th2/Th17 Responses Induced by Plant Oil Adjuvant-Based B. bronchiseptica Vaccine in Mice, with Mechanisms Unraveled by RNA-Seq, 16S rRNA and Metabolomics.

The current Bordetella bronchiseptica (Bb) vaccine, when adjuvanted with alum, does not elicit adequate robust cellular immunity or effective antibody defense against Bb attacks. Unfortunately, antibiotic treatment generally represents an ineffective strategy due to the development of resistance against a broad range of antibiotics. The present study was designed to investigate the immune response, protective capabilities and underlying mechanisms of a plant oil-based adjuvant E515 formulated with inactivated Bb antigen as a potential vaccine candidate against Bordetella bronchiseptica. Immunization studies revealed that a combination of SO, VE and GS (E515) exhibited a good synergistic adjuvant effect. The E515 adjuvanted Bb vaccine was proven to be highly efficacious and induced a mixed Th1/Th2/Th17 immune response in mice, leading to a significant increase in Bb-specific IgG, IgG1 and IgG2a antibodies, proliferative lymphocyte responses and cytokine levels (by lymphocytes and serum) and effectively induced responses by CD4+ TE, TM cells and B cells. The E515 adjuvant significantly enhanced the immune protection provided by the Bb vaccine in a mice model, as indicated by a reduced bacterial burden in the lungs. Multi-omics sequencing analysis revealed that E515 functions as an adjuvant by modulating critical pathways, including cytokine-cytokine receptor interaction, the IL-17 signaling pathway and the chemokine signaling pathway. This modulation also included interactions with beneficial species of bacteria including Alistipes, Odoribacter and Colidextribacter, as well as energy and lipid-related metabolites, thus highlighting its role as an immunomodulatory agent. Collectively, our results demonstrate the huge potential of E515-Bb vaccine candidates, thus highlighting the vegetable oil original adjuvant E515 as a promising agent for the development of new veterinary vaccines.

Mapping Age Differences in Brain Energy Metabolites and Metabolic Markers of Cellular Membrane Production and Degradation With 31P Magnetic Resonance Spectroscopy.

Using Phosphorus Magnetic Resonance Spectroscopy (31P MRS), we examined five metabolites associated with brain energy cycle, and cellular membrane production and degradation in 11 brain regions of 48 children (age 6-15), and 80 middle-aged and older adults (age 52-87). Levels of phosphomonoesters (PMEs) and phosphodiesters (PDEs), gamma plus alpha adenosine triphosphate (γαATP), phosphocreatine (PCr) and inorganic phosphate (Pi), were residualized on the total amplitude value. PMEs were greater in children compared to adults, whereas PDEs showed the opposite age difference. Higher γαATP and lower Pi were found in children compared to adults. The age group differences were particularly salient in the association cortices and anterior white matter. Among children, age correlated negatively with PMEs and positively with PDEs in association cortices. Compared to children, adults had lower intracellular pH. The results suggest reduction in membrane synthesis and increase in membrane degradation in adolescents and to a greater degree in adults compared to younger children. Concomitant reduction in γαATP and increase in Pi are consistent with reduced energy consumption in adolescents and further drop in middle-aged and older adults, although it is impossible to distinguish declines in energy supply from reduced demand due to shrinking neuropil, without longitudinal studies.

Xianglian pill alleviates ulcerative colitis by inhibiting M1 macrophage polarization via modulation of energy metabolite itaconate

BackgroundXianglian pill (XLP) is a traditional Chinese medicine (TCM) that is widely used to treat ulcerative colitis (UC). However, its mechanism of action in UC is unclear. PurposeThis study aimed to investigate the mechanism of action of XLP in treating UC and role of M1 macrophage polarization in this process. Study DesignIn vivo experiments were performed using UC mice while in vitro experiments were conducted using RAW264.7 cells. MethodsMice were administered 3% dextran sulfate to induce UC model and then treated with XLP. Changes in histopathology and pro-inflammatory cytokines were evaluated. The levels of M1 macrophages in mesenteric lymph nodes were detected by flow cytometry. Colon metabolite levels were analyzed using an energy metabolomic assay. To assess itaconate's impact, both in vivo (mice) and in vitro (RAW264.7 cells) models were employed. Immunofluorescence staining was used to measure the expression levels of TNF-α, IL-6, and iNOS, while qRT-PCR was utilized to quantify the mRNA levels of TET2, STAT1, and Nfkbiz. ResultsXLP alleviated ulcerative damage and reduced TNF-α and IL-6 levels in colon, and also downregulated the levels of M1 macrophages and modulated the state of energy metabolism. Specifically, XLP significantly increased ITA level in colonic tissue and this increase was significantly associated with decreased levels of M1 macrophages and alleviation of UC following XLP treatment. Moreover, ITA directly suppressed the polarization of macrophage from M0 to M1 phenotype, accompanied by the decrease of TNF-α, IL-6, and iNOS levels. Further, ITA decreased inflammatory responses in M1 macrophage by inhibiting the TET2/STAT1 and TET2/NF-κB signaling pathways. ConclusionXLP can treat UC by suppressing M1 macrophage polarization via increasing the level of energy metabolite ITA.

Effect of betaine supplementation on immunity, energy, and lipid metabolites of growing Murrah buffalo calves

This study aimed to observe the effect of betaine (BET) supplementation on the growth, immunity, energy, and lipid metabolites of Murrah buffalo calves. Twenty-one Murrah buffalo calves were taken and randomly distributed into three groups (n=3) after blocking by body weight (98.70±1.31 kg) and age (8.12±0.55 months). The feeding regimen was the same in all the groups except that the Treatment groups were supplemented additionally with 0.0 (B0), 7.0 (B7), and 14.0 (B14) g/d BET in three respective groups for 90 d of the experiment period. Total leukocytes (TLC), neutrophils, lymphocytes, total immunoglobulin (TIG), total antioxidant activity (TAA), energy, and lipid metabolites were observed at fortnightly intervals during 90 d experimental periods. Adding BET up to 14 g/d did not exert (P>0.05) any effect on total leukocytes and neutrophils concentration. Lymphocytes, TIG, and TAA were increased significantly (P<0.05) in BET received groups either dose 7 or 14 g/d than in the control. No effect of dietary addition of BET was observed on the glucose, non-esterifies fatty acid (NEFA), total cholesterol (TCH), and high-density lipoprotein cholesterol (HDL-CH). The results of our study indicate that supplemental BET may play a role in regulating the immunity of growing Murrah buffalo calves.

Targeting ketone body metabolism to treat fatty liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disorder marked by excessive accumulation of lipids within the liver. If untreated, this condition can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC). Given the liver's pivotal role in glucose and fatty acid metabolism, disruptions in these processes are commonly observed in MASLD. Ketone bodies, crucial energy metabolites primarily produced in the liver, are also closely related to the progression of MASLD. Recent studies have demonstrated that disrupted ketogenesis not only accompanies MASLD, but may also play a causal role in its development and progression. Moreover, activation of the ketogenic pathway has been suggested as a promising strategy for reducing excessive hepatic fat accumulation. This review focuses on the regulation of ketogenesis in MASLD, emphasizing the significance of dietary and pharmacological interventions as potential therapeutic approaches to treat fatty liver disease.

Metabolic Dysregulation and Metabolite Imbalances in Acute-on-chronic Liver Failure: Impact on Immune Status.

Liver failure encompasses a range of severe clinical syndromes resulting from the deterioration of liver function, triggered by factors both within and outside the liver. While the definition of acute-on-chronic liver failure (ACLF) may vary by region, it is universally recognized for its association with multiorgan failure, a robust inflammatory response, and high short-term mortality rates. Recent advances in metabolomics have provided insights into energy metabolism and metabolite alterations specific to ACLF. Additionally, immunometabolism is increasingly acknowledged as a pivotal mechanism in regulating immune cell functions. Therefore, understanding the energy metabolism pathways involved in ACLF and investigating how metabolite imbalances affect immune cell functionality are crucial for developing effective treatment strategies for ACLF. This review methodically examined the immune and metabolic states of ACLF patients and elucidated how alterations in metabolites impact immune functions, offering novel perspectives for immune regulation and therapeutic management of liver failure.

PSI-14 Serum energy metabolite and mineral concentrations in a contemporary flock of Western white-faced ewes during the periparturient period

Abstract Ewe prolificacy and litter weight has increased in Western U.S. sheep flocks potentially leading to greater prevalence of metabolic dysfunction around the periparturient period. Thus, the objective of this research was to quantify serum energy metabolites and minerals in a flock of Rambouillet ewes. A total of 56 ewes [2 to 5 yr; 92.4 ± 0.56 kg body weight (BW] with an average litter size (NLB) of 1.84 ± 0.08 (single n = 15, 27%; twin n = 35, 62%; triplet n = 6, 11%) were evaluated. Blood was collected on d -21, -14, -7, 0, 7, 14, 21, 28 relative to parturition. Serum concentrations of glucose, β-hydroxybutyrate (BHBA), non-esterified fatty acids (NEFA), and minerals were quantified. Data were analyzed as repeated measures with fixed effects of ewe age (2 to 5 yr), sampling timepoint, NLB (1 or ≥ 2), and their interactions. There was a NLB x sampling timepoint interaction for serum Cl where multiple bearing ewes had greater concentration at d -14 (P = 0.03) and single bearing ewes had greater concentration on d -7 (P = 0.01; Figure 1). The NLB x ewe age interaction was significant for serum Fe where concentrations were greater for multiple than single bearing 4-yr-old ewes but greater for single than multiple bearing 5-yr-old ewes (Figure 1; P ≤ 0.05). As main effects (Table 1), 2-yr-old ewes had greater serum glucose than 4-yr-old ewes (P = 0.04), and 4-yr-old ewes had greater serum Ca than 3-yr-old ewes (P = 0.02). Multiple bearing ewes had had greater BHBA and NEFA (P ≤ 0.001) than single bearing ewes. Proportions of ewes within normal concentrations of key serum elements were glucose (single: 100%, multiple: 95%); BHBA (single: 100%, multiple: 49%); NEFA (single: 93%, multiple: 37%); and Ca (single: 100%, multiple: 100%). Serum BHBA and NEFA peaked at d 14, while serum K, Na, Co, Mn, and Mo peaked at d -21. Serum Se was least at d -21 and peaked at d 0. Pearson correlation coefficients were estimated between average serum metabolite concentrations before parturition (PRE; d -21, -14, -7) and after parturition (POST; d 7, 14, 21, 28; Table 2). A moderate positive correlation between PRE-Glucose and POST-Glucose (P = 0.03) and strong negative correlations between PRE-Glucose and PRE-BHBA and PRE-Glucose and PRE-NEFA were observed (P ≤ 0.001). Additionally, BHBA and NEFA were positively correlated within the PRE and POST timepoints (P < 0.001). Ewe age and NLB drive metabolic demands during different timepoints in the periparturient period. Litter size does contribute to increased BHBA and NEFA, increasing the risk for pregnancy toxemia. Increased nutritional intervention of prolific, semi-extensively managed Western white-faced ewes should be considered to reduce the risk of metabolic stress.

From BBB to PPP: Bioenergetic requirements and challenges for oligodendrocytes in health and disease.

Mature myelinating oligodendrocytes, the cells that produce the myelin sheath that insulates axons in the central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy to execute action potentials, while the energy needs of oligodendrocytes are directed toward building the lipid-rich components of myelin and supporting neuronal metabolism by transferring glycolytic products to axons as additional fuel. The utilization of energy metabolites in the brain parenchyma is tightly regulated to meet the needs of different cell types. Disruption of the supply of metabolites can lead to stress and oligodendrocyte injury, contributing to various neurological disorders, including some demyelinating diseases. Understanding the physiological properties, structures, and mechanisms involved in oligodendrocyte energy metabolism, as well as the relationship between oligodendrocytes and neighboring cells, is crucial to investigate the underlying pathophysiology caused by metabolic impairment in these disorders. In this review, we describe the particular physiological properties of oligodendrocyte energy metabolism and the response of oligodendrocytes to metabolic stress. We delineate the relationship between oligodendrocytes and other cells in the context of the neurovascular unit, and the regulation of metabolite supply according to energetic needs. We focus on the specific bioenergetic requirements of oligodendrocytes and address the disruption of metabolic energy in demyelinating diseases. We encourage further studies to increase understanding of the significance of metabolic stress on oligodendrocyte injury, to support the development of novel therapeutic approaches for the treatment of demyelinating diseases.

An acute handling challenge mobilizes glucose and free fatty acids in mountain Dark-eyed Juncos (Junco hyemalis oreganus)

Resource mobilization and reallocation is a major endpoint of the physiological response to acute challenges. However, energy metabolites have not been the focus of most field studies. Here, we characterized the glycemic and free fatty acid (FFA) response to an acute-handling challenge in a breeding, free-living, population of Mountain Dark-eyed Juncos ( Junco hyemalis oreganus) in Mono County, CA. Juncos ( n = 12) were trapped in seed-baited potter traps at Tioga Pass Meadow, coinciding with territory establishment and early nesting period. Blood samples were collected at 0, 15, and 30 min post-capture, and analysis showed Juncos mobilized both glucose and FFA in response to an acute handling challenge. Blood glucose levels were significantly higher than baseline at 15 min (42.6% increase) and 30 min post-capture (66.7% increase). FFA levels were also significantly higher than baseline at 15 min (29.2% increase) and 30 min post-capture (22% increase). We also measured morphometrics (e.g., wing chord length, tarsus length, etc.), fat, and mass for each individual to investigate the effects of body size and fat storage on energy mobilization using linear models. We found no significant effects of body size or fat and mass on FFA mobilization. However, body size had a significant effect on glucose mobilization, with larger individuals displaying a higher percent increase in glucose from baseline to 15 min. Additionally, we found an effect of sex on glucose mobilization, with males showing a higher percent increase in glucose from baseline to 15 min. These results suggest that energy mobilization capacity is influenced by body size and male Juncos may increase energy mobilization relative to females during the breeding season.

Mechanistic insights into metabolic function of dynamin-related protein 1

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue–specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, DRP1 deficiency induced the retention of nascent lipid droplets in ER, leading to perturbed overall lipid dynamics in the KO mice. Collectively, dysregulation of the dynamics of mitochondria, ER, and lipid droplets contributes to whole-body metabolic disorders, as evidenced by perturbations in energy metabolites. Our findings demonstrate that DRP1 plays diverse and critical roles in regulating energy metabolism within adipose tissue during the progression of obesity.

Lactylome Analysis Unveils Lactylation-Dependent Mechanisms of Stemness Remodeling in the Liver Cancer Stem Cells.

Lactate plays a critical role as an energy substrate, metabolite, and signaling molecule in hepatocellular carcinoma (HCC). Intracellular lactate-derived protein lysine lactylation (Kla) is identified as a contributor to the progression of HCC. Liver cancer stem cells (LCSCs) are believed to be the root cause of phenotypic and functional heterogeneity in HCC. However, the impact of Kla on the biological processes of LCSCs remains poorly understood. Here enhanced glycolytic metabolism, lactate accumulation, and elevated levels of lactylation are observed in LCSCs compared to HCC cells. H3K56la was found to be closely associated with tumourigenesis and stemness of LCSCs. Notably, a comprehensive examination of the lactylome and proteome of LCSCs and HCC cells identified the ALDOA K230/322 lactylation, which plays a critical role in promoting the stemness of LCSCs. Furthermore, this study demonstrated the tight binding between aldolase A (ALDOA) and dead box deconjugate enzyme 17 (DDX17), which is attenuated by ALDOA lactylation, ultimately enhancing the regulatory function of DDX17 in maintaining the stemness of LCSCs. This investigation highlights the significance of Kla in modulating the stemness of LCSCs and its impact on the progression of HCC. Targeting lactylation in LCSCs may offer a promising therapeutic approach for treating HCC.

Tuberculosis-related Mood Disorders: Probiotics as a Next-Generation Strategy

Introduction: Tuberculosis-related mood disorders are well-known but least researched. As frequent comorbidity of tuberculosis (TB), depression is linked to poor adherence to treatment for a number of illnesses. The exact causal mechanism and pathways behind TB disease and associated mental illnesses are unclear. The disease's severity and duration impact the occurrence of depression, and MDR-TB enhances this risk. To summarise the information on the association between depression and unfavourable outcomes of TB treatment, we carried out a narrative review. Objective: The objective of this study is to provide an overview of probiotics as a cutting-edge treatment for mood disorders linked to tuberculosis. Methods: A systematic stepwise online database research was done for systematic reviews, original studies, and review papers published on probiotics and mental disorders associated with tuberculosis in PubMed/MEDLINE, Google Scholar, and Web of Science. The reference lists for these articles were also used as sources for the bibliography Results: The gut microbiota and the brain are connected by neuroendocrine-immune pathways. The diversity and abundance of microbiota Proteobacteria, Actinobacteria Bacteroides, and Firmicutes are reduced in tuberculosis patients. Through the stimulation of different immunological responses or visceral sensory pathways, these changes in the gut microbiome may be a contributing factor in emotional instability and mood disorders. Probiotics also lessen the stress response caused by cortisol, in addition to releasing neurotransmitters, including GABA, serotonin, noradrenaline, acetylcholine, and dopamine, in various brain regions. Probiotics are the most prevalent in the sensory brain network of the brain, which controls the brain's core processing of emotions and sensations. In addition, they produce short-chain fatty acids (SCAFs) from the bacterial fermentation of fibre in the colon, such as butyrate, which inhibits histone deacetylase, binds to G protein-coupled receptors, and serves as an energy metabolite. Butyrate plays a significant role in maintaining brain health by having antimanic and antidepressant effects. Several clinical research on patients with MDD has revealed that probiotics have favourable effects on depressive symptoms. Conclusion: The central dopamine system, inflammation, the BDNF system, and the gut-brain axis are all recognised to play crucial roles in the pathogenesis of MDD. Commercial probiotics that generate butyrate-producing SCFAs and those resistant to metabolic disorders (such as Bacteroidetes) may be beneficial for tuberculosis-related MDD during and after treatment. In this situation, using bacteria that produce SCFA could be a cutting-edge method of treating clinical MDD.

Citrate Promotes Nitric Oxide Production during Human Sperm Capacitation.

Sperm capacitation is a complex process essential for the spermatozoon to recognize and fertilize the oocyte. For capacitation to occur, human spermatozoa require low levels of reactive oxygen species (ROS), increased protein tyrosine phosphorylation, and sufficient levels of energy metabolites such as citrate. Human spermatozoa are exposed to high concentrations of citrate from the seminal plasma, yet the role of citrate in sperm capacitation is largely unknown. We report that citrate can support capacitation in human spermatozoa incubated with no other energy metabolites in the capacitation medium. Reduced capacitation levels were observed in spermatozoa incubated with inhibitors of mitochondrial citrate transporter (CIC), cytosolic ATP-citrate lyase (ACLY), malic enzyme (ME), and nitric oxide synthase (NOS). The role of citrate metabolism in ROS production was further elucidated as citrate increased NO● production in capacitated spermatozoa, whereas inhibition of ACLY reduced NO● production. This research characterizes a novel metabolic pathway for citrate to produce NO● in the process of human sperm capacitation.

Deacetylation of GLUD1 maintains the survival of lung adenocarcinoma cells under glucose starvation by inhibiting autophagic cell death

Enhanced glutamine catabolism is one of the main metabolic features of cancer, providing energy and intermediate metabolites for cancer progression. However, the functions of glutamine catabolism in cancer under nutrient deprivation need to be further clarified. Here, we discovered that deacetylation of glutamate dehydrogenase 1 (GLUD1), one of the key enzymes in glutamine catabolism, maintains the survival of lung adenocarcinoma (LUAD) cells under glucose starvation by inhibiting autophagic cell death. We found that glucose starvation increased GLUD1 activity by reducing its acetylation on Lys84 and promoted its active hexamer formation. Besides, deacetylation of GLUD1 induced its cytoplasmic localization, where GLUD1 was ubiquitinated in K63-linkage by TRIM21, leading to the binding of GLUD1 with cytoplasmic glutaminase KGA. These two effects enhanced glutamine metabolism both in mitochondria and cytoplasm, increased the production of alpha-ketoglutarate (α-KG). Meanwhile, cytoplasmic GLUD1 also interacted with p62 and prevented its acetylation, leading to the inhibition of p62 body formation. All these effects blocked autophagic cell death of LUAD cells under glucose starvation. Taken together, our results reveal a novel function of GLUD1 under glucose deprivation in LUAD cells and provide new insights into the functions of glutamine catabolism during cancer progression.

Environmentally relevant concentrations of microplastics from agricultural mulch and cadmium negatively impact earthworms by triggering neurotoxicity and disrupting homeostasis

Recent research has highlighted the ecological risk posed by microplastics (MPs) from mulching film and heavy metals to soil organisms. However, most studies overlooked real environmental levels of MPs and heavy metals. To address this gap, pristine and aged polyethylene (PE) mulching film-derived MPs (PMPs, 500 mg/kg; AMPs, 500 mg/kg) were combined with cadmium (Cd, 0.5 mg/kg) to assess the acute toxicity to earthworms and investigate associated molecular mechanisms (oxidative stress, osmoregulation pressure, gut microbiota, and metabolic responses) at environmentally relevant concentrations. Compared to Cd alone and Cd + PMPs treatments (11.15 ± 4.19 items/g), Cd + AMPs treatment resulted in higher MPs bioaccumulation (23.73 ± 13.14 items/g), more severe tissue lesions, and increased cell membrane osmotic pressure in earthworms’ intestines. Cd + AMPs induced neurotoxicity through elevated levels of glutamate and acetylcholinesterase. Earthworm intestines (0.98 ± 0.49 to 3.33 ± 0.37 mg/kg) exhibited significantly higher Cd content than soils (0.19 ± 0.01 to 0.51 ± 0.06 mg/kg) and casts (0.15 ± 0.01 to 0.25 ± 0.05 mg/kg), indicating PE-MPs facilitated Cd transport in earthworms’ bodies. Metabolomic analysis showed Cd + AMPs exposure depleted energy and nucleotide metabolites, disrupted cell homeostasis more profoundly than Cd and Cd + PMPs treatments. Overall, co-exposure to AMPs + Cd induced more severe neurotoxicity and disruption of homeostasis in earthworm than Cd and PMPs + Cd treatments. Our study, using Cd and MPs with environmental relevance, underscores MPs’ role in amplifying Cd accumulation and toxicity in earthworms.

High-Throughput Metabolite Analysis of Unicellular Microalgae by Orthogonal Hybrid Ionization Label-Free Mass Cytometry.

Microalgae metabolite analysis is fundamental for the rational design of metabolic engineering strategies for the biosynthesis of high-value products. Mass spectrometry (MS) has been utilized for single-cell microalgae analysis. However, limitations in the detection throughput and polarities of detectable substances make it difficult to realize high-throughput screening of high-performance microalgae. Herein, a plasma-assisted label-free mass cytometry, named as PACyESI-MS, was proposed combining the advantages of orthogonal hybrid ionization and high-throughput MS analysis, which realized rapid metabolite detection of single microalgae. The cell detection throughput of PACyESI-MS was up to 52 cells/min. Dozens of the critical primary and secondary metabolites within single microalgae were detected simultaneously, including pigments, lipids, and energy metabolites. Furthermore, metabolite changes of Chlamydomonas reinhardtii and Haematococcus pluvialis under nitrogen deficiency stress were studied. Discrimination of Chlamydomonas under different nutrient conditions was realized using single-cell metabolite profiles obtained by PACyESI-MS. The relationships between the accumulation of bioactive astaxanthin and changes in functional primary metabolites of Haematococcus were investigated. It was demonstrated that PACyESI-MS can detect the flexible change of metabolites in single microalgae cells under different nutritional conditions and during the synthesis of high-value products, which is expected to become an important tool for the design of metabolic engineering-based high-performance microalgae factories.

Chronic effects of exposure to polyethylene microplastics may be mitigated at the expense of growth and photosynthesis in reef-building corals

The causes of the physiological effects of microplastic pollution, potentially harming reef-building corals, are unclear. Reasons might include increased energy demands for handling particles and immune reactions. This study is among the first assessing the effects of long-term microplastic exposure on coral physiology at realistic concentrations (200 polyethylene particles L−1). The coral species Acropora muricata, Pocillopora verrucosa, Porites lutea, and Heliopora coerulea were exposed to microplastics for 11 months, and energy reserves, metabolites, growth, and photosymbiont state were analyzed. Results showed an overall low impact on coral physiology, yet species-specific effects occurred. Specifically, H. coerulea exhibited reduced growth, P. lutea and A. muricata showed changes in photosynthetic efficiency, and A. muricata variations in taurine levels. These findings suggest that corals may possess compensatory mechanisms mitigating the effects of microplastics. However, realistic microplastic concentrations only occasionally affected corals. Yet, corals exposed to increasing pollution scenarios will likely experience more negative impacts.

Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819–60.761)) and mortality (HR 3.418, 95% CI (1.308–8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (MPC1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (ERRα). Consequently, ERRα exhibits weakened binding to the MPC1 promoter. This outcome arises from the impaired interaction between ERRα and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of MPC1 and ERRα and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.