Similar Metabolic Patterns Research Articles

Ischemia-Induced Metabolic Patterns Associate With Kidney Function During Normothermic Kidney Perfusion, a Preclinical Study.

To investigate if ischemia alters donor kidney metabolism and whether these changes associate with organ function. An unmet need in kidney transplantation is the ability to predict post-transplant organ function before transplantation. Key to such viability testing is a profound understanding of the organ's complex biochemistry and how ischemia, inevitable during the transplantation process, influences this. First, metabolic changes in glucose, lactate and 20 amino acids induced by no, 1h of warm, or 22h of cold ischemia were investigated during 4h perfusion of pig kidneys with autologous whole blood (n=6/group), simulating the ischemia-reperfusion phase of transplantation. Next, we confirmed similar metabolic changes during normothermic preservation of pig (n=3/group; n=4 for cold ischemia) and discarded human kidneys (n=6) perfused with a red-blood cell based perfusate. At 2h of perfusion with autologous whole blood, abundances of 17/20 amino acids were significantly different between groups, reflecting the type of ischemia. Amino acid changes at 15 min and 2h of perfusion correlated with future kidney function during perfusion. Similar metabolic patterns were observed during perfusion preservation of pig and discarded human donor kidneys, suggesting an opportunity to assess kidney viability before transplantation. Perfusate metabolite changes during normothermic kidney perfusion represent a unique non-invasive opportunity to assess graft viability. These findings now need validation in transplant studies.

The Influence of Adipocyte Secretome on Selected Metabolic Fingerprints of Breast Cancer Cell Lines Representing the Four Major Breast Cancer Subtypes.

Molecular subtype (MS) is one of the most used classifications of breast cancer (BC). Four MSs are widely accepted according to receptor expression of estrogen, progesterone, and HER2. The impact of adipose tissue on BC MS metabolic impairment is still unclear. The present work aims to elucidate the metabolic alterations in breast cancer cell lines representing different MSs subjected to adipocyte associated factors. Preadipocytes isolated from human subcutaneous adipose tissue were differentiated into mature adipocytes. MS representative cell lines were exposed to mature adipocyte secretome. Extracellular medium was collected for metabolomics and RNA was extracted to evaluate enzymatic expression by RT-PCR. Adipocyte secretome exposure resulted in a decrease in the Warburg effect rate and an increase in cholesterol release. HER2+ cell lines (BT-474 and SK-BR-3) exhibited a similar metabolic pattern, in contrast to luminal A (MCF-7) and triple negative (TN) (MDA-MB-231), both presenting identical metabolisms. Anaplerosis was found in luminal A and TN representative cells, whereas cataplerotic reactions were likely to occur in HER2+ cell lines. Our results indicate that adipocyte secretome affects the central metabolism distinctly in each BC MS representative cell line.

The Possible Effect of Dietary Fiber Intake on the Metabolic Patterns of Dyslipidemia Subjects: Cross-Sectional Research Using Nontargeted Metabolomics

BackgroundDyslipidemia is important because of its association with various metabolic complications. Numerous studies have sought to obtain scientific evidence for managing dyslipidemia patients. ObjectivesThis study aims to identify differences in the nutritional traits of dyslipidemia subjects based on metabolite patterns. MethodsDyslipidemia (n = 73) and control (n = 80) subjects were included. Dyslipidemia was defined as triglycerides ≥200 mg/dL, total cholesterol ≥240 mg/dL, low density lipoprotein cholesterol ≥160 mg/dL, high-density lipoprotein cholesterol <40 mg/dL (men) or 50 mg/dL (women), or lipid-lowering medicine use. Nontargeted metabolomics based on ultra-high performance liquid chromatography–mass spectrometry identified plasma metabolites, and K-means clustering was used to reconstitute groups based on the similarity of metabolomic patterns across all subjects. Then, with eXtreme Gradient Boosting, metabolites significantly contributing to the new grouping were selected. Statistical analysis was conducted to analyze traits demonstrating appreciable differences between the groups. ResultsDyslipidemia subjects were divided into 2 groups based on whether they were (n = 24) or were not (n = 56) in a similar metabolic state as the controls by K-means clustering. The considerable contribution of 4 metabolites (3-hydroxybutyrylcarnitine, 2-octenal, 1,3,5-heptatriene, and 5β-cholanic acid) to this new subset of dyslipidemia was confirmed by eXtreme Gradient Boosting. Furthermore, fiber intake was significantly higher in dyslipidemia subjects whose metabolic state was similar to that of the control than in the dissimilar group (P = 0.002). Moreover, significant correlations were observed between the 4 metabolites and fiber intake. Regression analysis determined that the ideal cutoff for fiber intake was 17.28 g/d. ConclusionsDyslipidemia patients who consume 17.28 g/d or more of dietary fiber may maintain similar metabolic patterns to healthy individuals, with substantial effects on the changes in the concentrations of 4 metabolites. Our findings could be applied to developing dietary guidelines for dyslipidemia patients.

Single-cell transcriptome analysis reveals heterogeneity and convergence of the tumor microenvironment in colorectal cancer.

Colorectal cancer (CRC) ranks second for mortality and third for morbidity among the most commonly diagnosed cancers worldwide. We aimed to investigate the heterogeneity and convergence of tumor microenvironment (TME) in CRC. We analyzed the single-cell RNA sequencing data obtained from the Gene Expression Omnibus (GEO) database and identified 8 major cell types and 25 subgroups derived from tumor, para-tumor and peripheral blood. In this study, we found that there were significant differences in metabolic patterns, immunophenotypes and transcription factor (TF) regulatory patterns among different subgroups of each major cell type. However, subgroups manifested similar lipid metabolic patterns, immunosuppressive functions and TFs module at the end of the differentiation trajectory in CD8+ T cells, myeloid cells and Fibroblasts. Meanwhile, TFs regulated lipid metabolism and immunosuppressive ligand-receptor pairs were detected by tracing the differentiation trajectory. Based on the cell subgroup fractions calculated by CIBERSORTx and bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA), we constructed an immune risk model and clinical risk model of CRC which presented excellent prognostic value. This study identified that the differentiation was accompanied by remodeling of lipid metabolism and suppression of immune function, which suggest that lipid remodeling may be an important trigger of immunosuppression. More importantly, our work provides a new perspective for understanding the heterogeneity and convergence of the TME and will aid the development of prognosis and immunotherapies of CRC patients.

Phenotypic and genomic assessment of the potential threat of human spaceflight-relevant Staphylococcus capitis isolates under stress conditions.

Previous studies have reported that spaceflight specific conditions such as microgravity lead to changes in bacterial physiology and resistance behavior including increased expression of virulence factors, enhanced biofilm formation and decreased susceptibility to antibiotics. To assess if spaceflight induced physiological changes can manifest in human-associated bacteria, we compared three spaceflight relevant Staphylococcus capitis isolates (DSM 111179, ISS; DSM 31028, clean room; DSM 113836; artificial gravity bedrest study) with the type strain (DSM 20326T). We tested the three strains regarding growth, colony morphology, metabolism, fatty acid and polar lipid pattern, biofilm formation, susceptibility to antibiotics and survival in different stress conditions such as treatment with hydrogen peroxide, exposure to desiccation, and irradiation with X-rays and UV-C. Moreover, we sequenced, assembled, and analyzed the genomes of all four strains. Potential genetic determinants for phenotypic differences were investigated by comparative genomics. We found that all four strains show similar metabolic patterns and the same susceptibility to antibiotics. All four strains were considered resistant to fosfomycin. Physiological differences were mainly observed compared to the type strain and minor differences among the other three strains. The ISS isolate and the bedrest study isolate exhibit a strong delayed yellow pigmentation, which is absent in the other two strains. Pigments were extracted and analyzed by UV/Vis spectroscopy showing characteristic carotenoid spectra. The ISS isolate showed the highest growth rate as well as weighted average melting temperature (WAMT) of fatty acids (41.8°C) of all strains. The clean room isolate showed strongest biofilm formation and a high tolerance to desiccation. In general, all strains survived desiccation better in absence of oxygen. There were no differences among the strains regarding radiation tolerance. Phenotypic and genomic differences among the strains observed in this study are not inevitably indicating an increased virulence of the spaceflight isolate. However, the increased growth rate, higher WAMT and colony pigmentation of the spaceflight isolate are relevant phenotypes that require further research within the human spaceflight context. We conclude that combining genetic analysis with classical microbiological methods allows the detailed assessment of the potential threat of bacteria in highly regulated and extreme environments such as spaceflight environments.

Mitochondrial transporter expression patterns distinguish tumor from normal tissue and identify cancer subtypes with different survival and metabolism

Transporters of the inner mitochondrial membrane are essential to metabolism. We demonstrate that metabolism as represented by expression of genes encoding SLC25 transporters differentiates human cancers. Tumor to normal tissue expression ratios for clear cell renal cell carcinoma, colon adenocarcinoma, lung adenocarcinoma and breast invasive carcinoma were found to be highly significant. Affinity propagation trained on SLC25 gene expression patterns from 19 human cancer types (6825 TCGA samples) and normal tissues (2322 GTEx samples) was used to generate clusters. They differentiate cancers from normal tissues. They also indicate cancer subtypes with survivals distinct from the total patient population of the cancer type. Probing the kidney, colon, lung, and breast cancer clusters, subtype pairs of cancers were identified with distinct prognoses and differing in expression of protein coding genes from among 2080 metabolic enzymes assayed. We demonstrate that SLC25 expression clusters facilitate the identification of the tissue-of-origin, essential to efficacy of most cancer therapies, of CUPs (cancer-unknown-primary) known to have poor prognoses. Different cancer types within a single cluster have similar metabolic patterns and this raises the possibility that such cancers may respond similarly to existing and new anti-cancer therapies.

Dynamic metabolic interactions and trophic roles of human gut microbes identified using a minimal microbiome exhibiting ecological properties

Microbe–microbe interactions in the human gut are influenced by host-derived glycans and diet. The high complexity of the gut microbiome poses a major challenge for unraveling the metabolic interactions and trophic roles of key microbes. Synthetic minimal microbiomes provide a pragmatic approach to investigate their ecology including metabolic interactions. Here, we rationally designed a synthetic microbiome termed Mucin and Diet based Minimal Microbiome (MDb-MM) by taking into account known physiological features of 16 key bacteria. We combined 16S rRNA gene-based composition analysis, metabolite measurements and metatranscriptomics to investigate community dynamics, stability, inter-species metabolic interactions and their trophic roles. The 16 species co-existed in the in vitro gut ecosystems containing a mixture of complex substrates representing dietary fibers and mucin. The triplicate MDb-MM’s followed the Taylor’s power law and exhibited strikingly similar ecological and metabolic patterns. The MDb-MM exhibited resistance and resilience to temporal perturbations as evidenced by the abundance and metabolic end products. Microbe-specific temporal dynamics in transcriptional niche overlap and trophic interaction network explained the observed co-existence in a competitive minimal microbiome. Overall, the present study provides crucial insights into the co-existence, metabolic niches and trophic roles of key intestinal microbes in a highly dynamic and competitive in vitro ecosystem.

Effect of chlorine sanitizer on metabolic responses of Escherichia coli biofilms “big six” during cross-contamination from abiotic surface to sponge cake

The effect of chlorine on Escherichia coli biofilm O157:H7 are well established; however, the effect on biofilm adhesion to food as well as the six emerging E. coli serotypes (“big six”) have not been fully understood. Chlorine sanitization with 1-min 100 mg/L was applied against seven pathogenic E. coli (O111, O121:H19, O45:H2, O26:H11, O103:H11, O145, and O157:H7) biofilms on high-density polyethylene (HDPE) and stainless steel (SS) coupons, respectively. Using sponge cake as a food model, the adhesion behavior was evaluated by comparison of bacteria transfer rate before and after treatment. Besides, the metabolic profiles of biofilms were analyzed by nuclear magnetic resonance (NMR) spectrometer. A significant decrease in transfer rate (79% decline on SS and 33% decline on HDPE) was recorded as well as the distinctive pattern between SS and HDPE coupons was also noticed, with a low population (6–7 log CFU/coupon) attached and low survivals (0–3 log CFU/coupon) upon chlorine on SS, while high population (7–8 log CFU/coupon) attached and high survivals (5–7 log CFU/coupon) on HDPE. Moreover, O121:H19 and O26:H11 demonstrated the highest resistance to chlorine with the least metabolic status and pathways affected. O103:H11, O145, and O111 followed similar metabolic patterns on both surfaces. Distinct metabolic patterns were found in O45:H2 and O157:H7, where the former had more affected metabolic status and pathways on SS but less on HDPE, whereas the latter showed an opposite trend. Overall, a potential contamination source of STEC infection in flour products was demonstrated and metabolic changes induced by chlorine were revealed by NMR-based metabolomics, which provides insights to avoid “big six” biofilms contamination in food.

Response of lipid molecular structure to dietary lipid type in Chinese mitten crab Eriocheir sinensis: A deep lipidomics analysis

Lipid molecules and fatty acids were analyzed using lipidomics to understand the change of lipid structure and metabolism in the hepatopancreas of Chinese mitten crab (Eriocheir sinensis). The crabs fed diets with four oil sources (palm oil, olive oil, safflower seed oil and purple perilla oil) for 8 weeks. Palmitic acid, oleic acid, linoleic acid, and linolenic acid were the most abundant fatty acids in these oil types, respectively. Sixteen lipid classes were identified in the hepatopancreas. Triglycerides, phosphatidylcholines, diacylglycerols, and phosphatidylethanolamines in hepatopancreas were analysis deeply in this study. The relative contents of main lipid classes in the hepatopancreas were all significantly influenced by dietary oil sources. A similar pattern of lipid metabolism was observed in the E. sinensis fed palm oil and olive oil diets with an increasing quantity of C18:2n-6 in sn-1, 3 of triglycerides. Polyunsaturated fatty acids were distributed mainly in the sn-1, 3 position in triglycerides and in the sn-2 position in diacylglycerols and phospholipids. The abundance of C18:3n-3 in the diet could not significantly increase the contents of EPA and DHA in the hepatopancreas. Meanwhile, there was no C18:3n-3 at the sn-1 and no C18:0 at the sn-2 positions in phosphatidylcholines. This study was the first attempt on using lipidomics in crustaceans to understand the impact of dietary oil source on the structure of lipids stored in crustaceans. It provides a new insight and theoretical basis to understand the mechanism on the difference in lipid composition in the diet and in the tissue of crustaceans.

A Robust Panel Based on Mitochondrial Localized Proteins for Prognostic Prediction of Lung Adenocarcinoma

Due to high energy and material metabolism requirements, mitochondria are frequently active in tumor cells. Our study found that the high energy metabolism status is positively correlated with the poor prognosis of patients with lung adenocarcinoma. We constructed a scoring system (mitoRiskscore) based on the gene expression of specific mitochondrial localized proteins through univariate and LASSO cox regression. It has been shown that high mitoRiskscore was correlated with a shorter survival time after surgery in patients with lung adenocarcinoma. Compared with the typical TNM grading system, the mitoRiskscore gene panel had higher prediction accuracy. A vast number of external verification results ensured its universality. Additionally, the mitoRiskscore could evaluate the metabolic pattern and chemotherapy sensitivity of the tumor samples. Lung adenocarcinoma with higher mitoRiskscore was more active in glycolysis, and oxidative phosphorylation expression of proliferation-related pathway genes was also significantly upregulated. In contrast, patients with low mitoRiskscore had similar metabolic patterns to normal tissues. In order to improve the accuracy of prediction ability and promote clinical usage, we developed a nomogram that combined mitoRiskscore and clinical prognostic factors to predict the 3-year, 5-year, and 10-year survival rates of patients. We also performed in vitro experiments to verify the function of the key genes in the mitoRiskscore panel. In conclusion, the mitoRiskscore scoring system may assist clinicians to judge the postoperative survival rate and chemotherapy of patients with lung adenocarcinoma.

SIRT5 deficiency enhances the proliferative and therapeutic capacities of adipose-derived mesenchymal stem cell via metabolic switching

Abstract Background Mesenchymal stem/stromal cells (MSCs) render potential therapies for multiple ischemic diseases. However, in vitro expansion of MSCs before application leads to a metabolic switch from glycolysis to oxidative phosphorylation, drastically impairing their proliferative and therapeutic capacities. Purpose Here we aim to identify the role of SIRT5, a master metabolic regulator, in culture expansion of adipose-derived MSCs (ADMSCs). Methods SIRT5 deficiencyADMSCs was obtained from Sirt5−/− mice and their metabolic pattern and proliferation capacity were tested during in vitro expansion. Hind limb ischemic model was established to evaluated the therapeutic function of Sirt5−/−ADMSCs. Results SIRT5 protein level was upregulated in ADMCSs undergoing culture expansion. Sirt5−/−ADMSCs during in vitro expansion exhibited higher proliferation rate, delayed senescence and enhanced antioxidant capacity. SIRT5 deficiency induced hypersuccinylation of metabolic-related proteins, leading to attenuated mitochondrial respiration with elevated glycolysis and pentose phosphate pathway. Furthermore, lowering succinylation level by glycine treatment reversed the altered metabolism and enhanced proliferation of Sirt5−/−ADMSCs. In mice hind limb ischemic model, SIRT5−/−ADMSCs treatment achieved better blood flow recovery and angiogenesis compared to WT ADMSCs treatment. Conclusion We reveal that SIRT5 is a key regulator of ADMSCs undergoing in vitro culture. Ablation of SIRT5 leads to reversed metabolic pattern, enhanced proliferative capacity and improved therapeutic outcomes. Our data provide a potential target for enhancing MSC functional properties during bio-manufacturing in future MSC therapy. Such work may not only benefit MSC cell therapy, but could extent to a wide variety of other stem cells that share similar metabolic pattern. Graphic Abstract Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Major Research Plan of the National Natural Science Foundation of China. National Science Fund for Distinguished Young Scholars.

Synchronized variations in levels of essential amino acids during germination in grain Amaranth

Seed germination is a fundamental process involving series of biochemical changes contributing to successful growth and development of new plant. Changes in the content observed during germination reflect developmental stages. Analyses of their behavior and profiles could provide insights into different strategies for regulating metabolism. In present study, seeds of A. hypochondriacus were germinated at controlled conditions and were used for estimation of total proteins and free amino acids. The estimation of amino acids was done at different time intervals throughout germination using LC MS/MS technique. The trends observed in content of individual free amino acids showed essential amino acid share a similar pattern of metabolism indicating coordinated regulation of amino acid pathways.

Characterizing the metabolites related to rice salt tolerance with introgression lines exhibiting contrasting performances in response to saline conditions

Rice is susceptible to salt stress at the seedling stage. To explore the molecular mechanisms underlying salt tolerance, the metabolic responses to salt stress were investigated with a metabolite-profiling technique. Gas chromatography–mass spectrometry was used to profile metabolite changes in five rice lines with a similar genetic background, but with obviously diverse growth performances under saline conditions. A total of 84 metabolites were detected in rice leaf extracts under control and saline conditions. The data revealed that amino acids were enriched more in three salt-tolerant lines (G58, G1710, and IR64) than in two salt-sensitive lines (G45 and G52) under control conditions, suggesting that there were basal metabolite differences between the tolerant and sensitive lines. Additionally, significantly higher allantoin levels in G58, G1710, and IR64 under both stress and control conditions were observed, implying allantoin was important for the better growth of the three rice lines. Moreover, sorbitol, melezitose, and pipecolic acid levels increased considerably in response to salt stress in the five lines, indicating they contribute to rice responses to salt stress significantly. Interestingly, the similar metabolic patterns were regulated by salt stress in the salt-sensitive and salt-tolerant lines, and the main difference was quantitative. The sensitive lines had more pronounced increases during the early stages of the stress treatment than the tolerant lines. Thus, monitoring the metabolome changes of plants may provide crucial insights into how plants tolerate stress. The results presented herein provide valuable information for further elucidating the molecular mechanisms underlying rice salt tolerance.

Electrochemical and in silico approaches for liver metabolic oxidation of antitumor-active triazoloacridinone C-1305

5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) is a promising antitumor compound developed in our laboratory. A better understanding of its metabolic transformations is still needed to explain the multidirectional mechanism of pharmacological action of triazoloacridinone derivatives at all. Thus, the aim of the current work was to predict oxidative pathways of C-1305 that would reflect its phase I metabolism. The multi-tool analysis of C-1305 metabolism included electrochemical conversion and in silico sites of metabolism predictions in relation to liver microsomal model. In the framework of the first approach, an electrochemical cell was coupled on-line to an electrospray ionization mass spectrometer. The effluent of the electrochemical cell was also injected onto a liquid chromatography column for the separation of different products formed prior to mass spectrometry analysis. In silico studies were performed using MetaSite software. Standard microsomal incubation was employed as a reference procedure. We found that C-1305 underwent electrochemical oxidation primarily on the dialkylaminoalkylamino moiety. An unknown N-dealkylated and hydroxylated C-1305 products have been identified. The electrochemical system was also able to simulate oxygenation reactions. Similar pattern of C-1305 metabolism has been predicted using in silico approach. Both proposed strategies showed high agreement in relation to the generated metabolic products of C-1305. Thus, we conclude that they can be considered as simple alternatives to enzymatic assays, affording time and cost efficiency.

Characterization and Detection of Leaf Photosynthetic Response to Citrus Huanglongbing from Cool to Hot Seasons in Two Orchards

HighlightsAn abnormal accumulation of sucrose and glucose was found in HLB-infected leaves, and it presented a similar pattern in different orchards from cool to hot seasons.A decreasing value of the actual quantum yield of PSII (FPSII) in HLB-infected leaves was mainly related to an increase of non-regulated energy quenching (FNO) due to the irreversible damage of PSII.Chlorophyll fluorescence imaging combined with a random forest was able to identify HLB at the asymptomatic stage.Abstract Citrus Huanglongbing (HLB) poses a serious threat to citrus production. This research aimed to explore chlorophyll fluorescence imaging for characterizing the photosynthetic response to HLB-infected citrus leaves in different orchards and seasons. Chlorophyll fluorescence images of citrus leaves were acquired with an in-house chlorophyll fluorescence imaging system. It was found that sucrose and glucose accumulated earlier than starch in HLB-infected leaves, and a similar carbohydrate metabolic pattern was observed in HLB-infected leaves grown in different orchards from cool to hot seasons. The pathogen damaged the thylakoid structure of chloroplasts with a higher value of Fo. It decreased photosynthetic activity of the host by reducing the number of active photosynthetic centers and the maximum quantum yield of PSII (Fv/Fm) with lower values of Fv/Fo and Fv/Fm. Additionally, the pathogen modified the allocation of excitation energy in citrus leaves by reducing the actual quantum yield of PSII (FPSII) due to an increase of non-regulated energy quenching (FNO), which indicated irreversible PSII damage before symptom development. Moreover, photosynthetic signatures combined with the random forest method were able to identify HLB in the asymptomatic stage with an overall accuracy of 91.8%. These results demonstrated the potential of chlorophyll fluorescence imaging for evaluating the photosynthetic response to HLB as well as disease diagnosis. Keywords: Carbohydrate metabolism, Chlorophyll fluorescence imaging, Citrus Huanglongbing, Photosynthetic efficiency, Random forest model.

Blockade of Glutathione Metabolism in IDH1-Mutated Glioma.

Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated cancer in vitro and in vivo Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated cancer treatment.

Quantitative multi-omics analysis of the effects of mitochondrial dysfunction on lipid metabolism in Saccharomyces cerevisiae.

In this study, combined genome, transcriptome, and metabolome analysis was performed for eight Saccharomyces cerevisiae mitochondrial respiration-deficient mutants. Each mutant exhibited a unique nuclear genome mutation pattern; the nuclear genome mutations, and thus potentially affected genes and metabolic pathways, showed a co-occurrence frequency of ≤ 3 among the eight mutants. For example, only a lipid metabolism-related pathway was likely to be affected by the nuclear genome mutationsin one of the mutants. However, large deletions in the mitochondrial genome were the shared characteristic among the eight mutants. At the transcriptomic level, lipid metabolism was the most significantly enriched Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway for differentially expressed genes (DEGs) co-occurring in both ≥ 4 and ≥ 5 mutants. Any identified DEG enriched in lipid metabolism showed the same up-/down-regulated pattern among nearly all eight mutants. Further, 126 differentially expressed lipid species (DELS) were identified, which also showed the same up-/down-regulated pattern among nearly all investigated mutants. It was conservatively demonstrated that the similar change pattern of lipid metabolism in the entire investigated mutant population was attributed to mitochondrial dysfunction. The change spectrum of lipid species was presented, suggesting that the number and change degree of up-regulated lipid species were higher than those of down-regulated lipid species. Additionally, energy storage lipids increased in content and plasma-membrane phospholipid compositions varied in the relative proposition. The results for the genome, transcriptome, and lipidome were mutually validated, which provides quantitative data revealing the roles of mitochondria from a global cellular perspective.

Metabolic perturbation of acrylate pathway in Lactobacillus plantarum

Engineering microbes with heterologous pathway for production of bio-based products has received considerable attention. Reconstituting such non-native pathway in addition to desired product formation often brings an allosteric modulation in enzymes competing at fragile nodes that result in by-product redistribution, in order to retain energy and redox balance. This work, Lactobacillus plantarum engineered with acrylate pathway for propionate production was studied under similar perspectives. Upon expression, the heterologous pathway did not result in propionic acid production under standard glucose concentration of 20 g/L, but 0.01 mM of propionate was formed when grown under low glucose concentration of 1 g/L. Further analysis of secreted metabolites with increased glucose concentration of 10 and 30 g/L remained futile towards propionate formation but showed reorientation in pyruvate metabolism which was related to the control imposed by the host to regulate the hidden constraints caused by gene perturbation. Further, it was ensured that the limitation of supplements did not play any functional role in inhibiting propionic acid synthesis but still followed similar metabolic pattern which was quite unclear though interpreted to certain extent. Thus, the findings gave insights into physiological and metabolic capabilities of Lactobacillus plantarum that at least in principle can be used to enhance the strain performance for increased propionic acid production.

An upper limit on Gibbs energy dissipation governs cellular metabolism.

The principles governing cellular metabolic operation are poorly understood. Because diverse organisms show similar metabolic flux patterns, we hypothesized that a fundamental thermodynamic constraint might shape cellular metabolism. Here, we develop a constraint-based model for Saccharomyces cerevisiae with a comprehensive description of biochemical thermodynamics including a Gibbs energy balance. Non-linear regression analyses of quantitative metabolome and physiology data reveal the existence of an upper rate limit for cellular Gibbs energy dissipation. By applying this limit in flux balance analyses with growth maximization as the objective function, our model correctly predicts the physiology and intracellular metabolic fluxes for different glucose uptake rates as well as the maximal growth rate. We find that cells arrange their intracellular metabolic fluxes in such a way that, with increasing glucose uptake rates, they can accomplish optimal growth rates but stay below the critical rate limit on Gibbs energy dissipation. Once all possibilities for intracellular flux redistribution are exhausted, cells reach their maximal growth rate. This principle also holds for Escherichia coli and different carbon sources. Our work proposes that metabolic reaction stoichiometry, a limit on the cellular Gibbs energy dissipation rate, and the objective of growth maximization shape metabolism across organisms and conditions.

Opposite subgenual cingulate cortical functional connectivity and metabolic activity patterns in refractory melancholic major depression.

Although in treatment-resistant depression (TRD) subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) is frequently used to examine deregulated brain networks, neurobiological data from other sources may be required to interpret these FC findings. In 16 melancholic TRD patients with a high level of treatment resistance and 16 closely matched healthy never-depressed individuals we verified whether sgACC FC patterns were related to regional metabolic activity (CMRglc) with 18FDG PET imaging. Notwithstanding that TRD patients displayed stronger sgACC FC with the right lateral frontotemporal cortex, metabolically they exhibited the opposite pattern. Our results indicate that the sgACC seed and its functionally connected regions not automatically follow a similar metabolic pattern in TRD, possibly reflecting the refractory state of the sample. Multimodal brain imaging may help to increase our insight into the pathophysiology of TRD.