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Proceedings of the National Academy of... Dec 2021Aerobic fermentation, also referred to as the Crabtree effect in yeast, is a well-studied phenomenon that allows many eukaryal cells to attain higher growth rates at...
Aerobic fermentation, also referred to as the Crabtree effect in yeast, is a well-studied phenomenon that allows many eukaryal cells to attain higher growth rates at high glucose availability. Not all yeasts exhibit the Crabtree effect, and it is not known why Crabtree-negative yeasts can grow at rates comparable to Crabtree-positive yeasts. Here, we quantitatively compared two Crabtree-positive yeasts, and , and two Crabtree-negative yeasts, and , cultivated under glucose excess conditions. Combining physiological and proteome quantification with genome-scale metabolic modeling, we found that the two groups differ in energy metabolism and translation efficiency. In Crabtree-positive yeasts, the central carbon metabolism flux and proteome allocation favor a glucose utilization strategy minimizing proteome cost as proteins translation parameters, including ribosomal content and/or efficiency, are lower. Crabtree-negative yeasts, however, use a strategy of maximizing ATP yield, accompanied by higher protein translation parameters. Our analyses provide insight into the underlying reasons for the Crabtree effect, demonstrating a coupling to adaptations in both metabolism and protein translation.
Topics: Aerobiosis; Fermentation; Fungal Proteins; Gene Expression Regulation, Fungal; Glucose; Mitochondrial Proton-Translocating ATPases; Proteome; Species Specificity; Yeasts
PubMed: 34903663
DOI: 10.1073/pnas.2112836118 -
Molecules (Basel, Switzerland) Nov 2021Lactate and isoprene are two common monomers for the industrial production of polyesters and synthetic rubbers. The present study tested the co-production of D-lactate...
Lactate and isoprene are two common monomers for the industrial production of polyesters and synthetic rubbers. The present study tested the co-production of D-lactate and isoprene by engineered in microaerobic conditions. The deletion of alcohol dehydrogenase () and acetate kinase () genes, along with the supplementation with betaine, improved the co-production of lactate and isoprene from the substrates of glucose and mevalonate. In fed-batch studies, microaerobic fermentation significantly improved the isoprene concentration in fermentation outlet gas (average 0.021 g/L), compared with fermentation under aerobic conditions (average 0.0009 g/L). The final production of D-lactate and isoprene can reach 44.0 g/L and 3.2 g/L, respectively, through fed-batch microaerobic fermentation. Our study demonstrated a dual-phase production strategy in the co-production of isoprene (gas phase) and lactate (liquid phase). The increased concentration of gas-phase isoprene could benefit the downstream process and decrease the production cost to collect and purify the bio-isoprene from the fermentation outlet gas. The proposed microaerobic process can potentially be applied in the production of other volatile bioproducts to benefit the downstream purification process.
Topics: Aerobiosis; Butadienes; Escherichia coli; Fermentation; Hemiterpenes; Lactic Acid; Metabolic Engineering; Mevalonic Acid
PubMed: 34885764
DOI: 10.3390/molecules26237173 -
International Journal of Molecular... Nov 2021Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount... (Review)
Review
Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.
Topics: Aerobiosis; Cell Communication; Glucose; Glycolysis; Humans; Melatonin; Mitochondria; Neoplasms; Warburg Effect, Oncologic
PubMed: 34830375
DOI: 10.3390/ijms222212494 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Oct 2021Biological denitrification is the most widely used technology for nitrate removal in wastewater treatment. Conventional denitrification requires long hydraulic retention...
Biological denitrification is the most widely used technology for nitrate removal in wastewater treatment. Conventional denitrification requires long hydraulic retention time, and the nitrate removal efficiency in winter is low due to the low temperature. Therefore, it is expected to develop new approaches to enhance the denitrification process. In this paper, the effect of adding different concentrations of Fe₃O₄ nanoparticles on the denitrification catalyzed by Pseudomonas stutzeri was investigated. The maximum specific degradation rate of nitrate nitrogen improved from 18.0 h⁻¹ to 23.7 h⁻¹ when the concentration of Fe₃O₄ increased from 0 mg/L to 4 000 mg/L. Total proteins and intracellular iron content also increased along with increasing the concentration of Fe₃O₄. RT-qPCR and label-free proteomics analyses showed that the relative expression level of denitrifying genes napA, narJ, nirB, norR, nosZ of P. stutzeri increased by 55.7%, 24.9%, 24.5%, 36.5%, 120% upon addition of Fe₃O₄, and that of denitrifying reductase Nap, Nar, Nir, Nor, Nos increased by 85.0%, 147%, 16.5%, 47.1%, 95.9%, respectively. No significant difference was observed on the relative expression level of denitrifying genes and denitrifying reductases between the bacteria suspended and the bacteria adhered to Fe₃O₄. Interestingly, the relative expression level of electron transfer proteins of bacteria adhered to Fe₃O₄ was higher than that of the bacteria suspended. The results indicated that Fe₃O₄ promoted cell growth and metabolism through direct contact with bacteria, thereby improving the denitrification. These findings may provide theoretical support for the development of enhanced denitrification.
Topics: Aerobiosis; Denitrification; Nitrates; Nitrogen; Pseudomonas stutzeri
PubMed: 34708620
DOI: 10.13345/j.cjb.210426 -
International Journal of Molecular... Oct 2021Glioma is the most common and aggressive tumor of the central nervous system. The uncontrolled proliferation, cellular heterogeneity, and diffusive capacity of glioma... (Review)
Review
Glioma is the most common and aggressive tumor of the central nervous system. The uncontrolled proliferation, cellular heterogeneity, and diffusive capacity of glioma cells contribute to a very poor prognosis of patients with high grade glioma. Compared to normal cells, cancer cells exhibit a higher rate of glucose uptake, which is accompanied with the metabolic switch from oxidative phosphorylation to aerobic glycolysis. The metabolic reprogramming of cancer cell supports excessive cell proliferation, which are frequently mediated by the activation of oncogenes or the perturbations of tumor suppressor genes. Recently, a growing body of evidence has started to reveal that long noncoding RNAs (lncRNAs) are implicated in a wide spectrum of biological processes in glioma, including malignant phenotypes and aerobic glycolysis. However, the mechanisms of diverse lncRNAs in the initiation and progression of gliomas remain to be fully unveiled. In this review, we summarized the diverse roles of lncRNAs in shaping the biological features and aerobic glycolysis of glioma. The thorough understanding of lncRNAs in glioma biology provides opportunities for developing diagnostic biomarkers and novel therapeutic strategies targeting gliomas.
Topics: Aerobiosis; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Glycolysis; Humans; Neoplastic Stem Cells; Prognosis; RNA, Long Noncoding; Signal Transduction
PubMed: 34681857
DOI: 10.3390/ijms222011197 -
Bioengineered Dec 2021In recent researches, circular RNAs (circRNAs) have been shown to exert critical functions in osteosarcoma biology. Nevertheless, the contribution of circRNAs to...
In recent researches, circular RNAs (circRNAs) have been shown to exert critical functions in osteosarcoma biology. Nevertheless, the contribution of circRNAs to osteosarcoma remains largely unclear. Results indicated that expression of circATRNL1 was higher in osteosarcoma tissues and cells. The high-expression of circATRNL1 was significantly correlated with aggressive features and acted as an independent risk factor for osteosarcoma patients' overall survival. Functionally, our findings demonstrate that circATRNL1 promotes the osteosarcoma aerobic glycolysis in vitro. Mechanistically, circATRNL1 up-regulated the expression level of LDHA, which was also targeted by miR-409-3p. Therefore, circATRNL1 exerted the accelerative roles of osteosarcoma aerobic glycolysis through miR-409-3p/LDHA axis. In conclusion, circATRNL1 promoted osteosarcoma progression by enhancing glycolysis via circATRNL1/miR-409-3p/LDHA axis, which may inspire a novel therapeutic target for osteosarcoma.
Topics: Aerobiosis; Animals; Base Sequence; Cell Line, Tumor; Female; Glycolysis; Humans; L-Lactate Dehydrogenase; Male; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Models, Biological; Osteosarcoma; Prognosis; RNA, Circular; Mice
PubMed: 34635009
DOI: 10.1080/21655979.2021.1985343 -
Food Microbiology Feb 2022Aerobic fermentation was previously proposed to reduce the ethanol content of wine. The main constraint found for Saccharomyces cerevisiae to be used under these...
Aerobic fermentation was previously proposed to reduce the ethanol content of wine. The main constraint found for Saccharomyces cerevisiae to be used under these conditions was the high levels of acetic acid produced by all S. cerevisiae strains previously tested. This work addressed the identification of S. cerevisiae wine yeast strains suitable for aerobic fermentation and the optimization of fermentation conditions to obtain a reduced ethanol yield with acceptable volatile acidity. This approach unveiled a great diversity in acetic acid yield for different S. cerevisiae strains under aerobic conditions, with some strains showing very low volatile acidity. Three strains were selected for further characterization in bioreactors, with natural grape must, under aerobic and anaerobic conditions. Ethanol yields were lower under aerobic than under anaerobic conditions for all strains, and acetic acid levels were low for two of them. Strain-dependent changes in volatile compounds were also observed between aerobic and anaerobic conditions. Finally, the process was optimized at laboratory scale for one strain. This is the first report of S. cerevisiae wine strains showing low acetic acid production under aerobic conditions and paves the way for simplified aerobic fermentation protocols aimed to reducing the alcohol content of wines.
Topics: Acetic Acid; Aerobiosis; Ethanol; Fermentation; Saccharomyces cerevisiae; Wine
PubMed: 34579853
DOI: 10.1016/j.fm.2021.103893 -
Life (Basel, Switzerland) Sep 2021Arc (anoxic redox control), one of the most intensely investigated two-component regulatory systems in γ-proteobacteria, plays a major role in mediating the metabolic...
Arc (anoxic redox control), one of the most intensely investigated two-component regulatory systems in γ-proteobacteria, plays a major role in mediating the metabolic transition from aerobiosis to anaerobiosis. In , a research model for respiratory versatility, Arc is crucial for aerobic growth. However, how this occurs remains largely unknown. In this study, we demonstrated that the loss of the response regulator ArcA distorts the correlation between transcription and translation by inhibiting the ribosome biosynthesis. This effect largely underlies the growth defect because it concurs with the effect of chloramphenicol, which impairs translation. Reduced transcription of ArcA-dependent ribosomal protein S1 appears to have a significant impact on ribosome assembly. We further show that the lowered translation efficiency is not accountable for the envelope defect, another major defect resulting from the ArcA loss. Overall, our results suggest that although the mutation impairs growth through multi-fold complex impacts in physiology, the reduced translation efficacy appears to be a major cause for the phenotype, demonstrating that Arc is a primary system that coordinates proteomic resources with metabolism in .
PubMed: 34575075
DOI: 10.3390/life11090926 -
Molecular Microbiology Oct 2021Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs). Successful urinary tract colonization requires appropriate...
Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs). Successful urinary tract colonization requires appropriate expression of virulence factors in response to host environmental cues, such as limited oxygen and iron availability. Hemolysin is a pore-forming toxin, and its expression correlates with the severity of UPEC infection. Previously, we showed that hemolysin expression is enhanced under anaerobic conditions; however, the genetic basis and regulatory mechanisms involved remain undefined. Here, a transposon-based forward screen identified bis-molybdopterin guanine dinucleotide cofactor (bis-MGD) biosynthesis as an important factor for a full transcription of hemolysin under anaerobiosis but not under aerobiosis. bis-MGD positively influences hemolysin transcription via c3566-c3568, an operon immediately upstream of and cotranscribed with hlyCABD. Furthermore, suppressor mutation analysis identified the nitrogen regulator NtrC as a direct repressor of c3566-c3568-hlyCABD expression, and intact bis-MGD biosynthesis downregulated ntrC expression, thus at least partially explaining the positive role of bis-MGD in modulating hemolysin expression. Finally, bis-MGD is involved in hemolysin-mediated uroepithelial cell death and contributes to the competitive fitness of UPEC in a murine model of UTI. Collectively, our data establish that bis-MGD biosynthesis plays a crucial role in UPEC fitness in vivo, thus providing a potential target for combatting UTIs.
Topics: Anaerobiosis; Animals; Cell Death; Cell Line; Escherichia coli Infections; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Guanine Nucleotides; Hemolysin Proteins; Humans; Mice; Mice, Inbred CBA; Mutagenesis, Insertional; Operon; PII Nitrogen Regulatory Proteins; Pterins; Transcription Factors; Transcriptome; Uropathogenic Escherichia coli; Virulence; Virulence Factors
PubMed: 34494331
DOI: 10.1111/mmi.14809 -
Molecular Neurodegeneration Sep 2021Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele... (Comparative Study)
Comparative Study
BACKGROUND
Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.
METHODS
Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.
RESULTS
Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis.
CONCLUSIONS
Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.
Topics: Adolescent; Adult; Aerobiosis; Aged; Alzheimer Disease; Animals; Apolipoprotein E4; Astrocytes; Base Sequence; Brain Chemistry; Cells, Cultured; Early Diagnosis; Energy Metabolism; Female; Gas Chromatography-Mass Spectrometry; Gene Knock-In Techniques; Glucose; Glycolysis; Humans; Metabolomics; Mice; Mice, Transgenic; Middle Aged; Nerve Tissue Proteins; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; Prodromal Symptoms; Sex Characteristics; Single-Cell Analysis; Young Adult
PubMed: 34488832
DOI: 10.1186/s13024-021-00483-y