-
ELife May 2024Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as the potato blight , and the...
Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as the potato blight , and the human intestinal protozoan . In most eukaryotes, glycolysis is a strictly cytosolic metabolic pathway that converts glucose to pyruvate, resulting in the production of NADH and ATP (Adenosine triphosphate). In contrast, stramenopiles have a branched glycolysis in which the enzymes of the pay-off phase are located in both the cytosol and the mitochondrial matrix. Here, we identify a mitochondrial carrier in that can transport glycolytic intermediates, such as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, across the mitochondrial inner membrane, linking the cytosolic and mitochondrial branches of glycolysis. Comparative analyses with the phylogenetically related human mitochondrial oxoglutarate carrier (SLC25A11) and dicarboxylate carrier (SLC25A10) show that the glycolytic intermediate carrier has lost its ability to transport the canonical substrates malate and oxoglutarate. lacks several key components of oxidative phosphorylation required for the generation of mitochondrial ATP, such as complexes III and IV, ATP synthase, and ADP/ATP carriers. The presence of the glycolytic pay-off phase in the mitochondrial matrix generates ATP, which powers energy-requiring processes, such as macromolecular synthesis, as well as NADH, used by mitochondrial complex I to generate a proton motive force to drive the import of proteins and molecules. Given its unique substrate specificity and central role in carbon and energy metabolism, the carrier for glycolytic intermediates identified here represents a specific drug and pesticide target against stramenopile pathogens, which are of great economic importance.
Topics: Blastocystis; Glycolysis; Humans; Mitochondria; Cytosol; Biological Transport; Protozoan Proteins
PubMed: 38780415
DOI: 10.7554/eLife.94187 -
Human Molecular Genetics May 2024The mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of energy required by cells. Given the mitochondrion's endosymbiotic origin, the OXPHOS... (Review)
Review
The mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of energy required by cells. Given the mitochondrion's endosymbiotic origin, the OXPHOS machinery is still under dual genetic control where most OXPHOS subunits are encoded by the nuclear DNA and imported into mitochondria, while a small subset is encoded on the mitochondrion's own genome, the mitochondrial DNA (mtDNA). The nuclear and mtDNA encoded subunits must be expressed and assembled in a highly orchestrated fashion to form a functional OXPHOS system and meanwhile prevent the generation of any harmful assembly intermediates. While several mechanisms have evolved in eukaryotes to achieve such a coordinated expression, this review will focus on how the translation of mtDNA encoded OXPHOS subunits is tailored to OXPHOS assembly.
Topics: Oxidative Phosphorylation; Mitochondria; Humans; DNA, Mitochondrial; Protein Biosynthesis; Animals
PubMed: 38779773
DOI: 10.1093/hmg/ddae025 -
Nature Jun 2024Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily. Their dysfunction is...
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome. Earlier studies concluded that FLVCR1 may function as a haem exporter, whereas FLVCR2 was suggested to act as a haem importer, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.
Topics: Humans; Binding Sites; Biological Transport; Cations; Cell Membrane; Choline; Ethanolamine; Membrane Transport Proteins; Models, Molecular; Protein Conformation; Receptors, Virus; Substrate Specificity; Tryptophan; Tyrosine; Mutation
PubMed: 38778100
DOI: 10.1038/s41586-024-07444-7 -
Current Developments in Nutrition May 2024Dietary assessment is a fundamental component of nutrition research and plays a pivotal role in managing chronic diseases. Traditional dietary assessment methods,...
BACKGROUND
Dietary assessment is a fundamental component of nutrition research and plays a pivotal role in managing chronic diseases. Traditional dietary assessment methods, particularly in the context of Thai cuisine, often require extensive training and may lead to estimation errors.
OBJECTIVES
To address these challenges, Institute of Nutrition, Mahidol University (INMU) iFood, an innovative artificial intelligence-based Thai food dietary assessment system, allows for estimating the nutritive values of dishes from food images.
METHODS
INMU iFood leverages state-of-the-art technology and integrates a validated automated Thai food analysis system. Users can use 3 distinct input methods: food image recognition, manual input, and a convenient barcode scanner. This versatility simplifies the tracking of dietary intake while maximizing data quality at the individual level. The core improvement in INMU iFood can be attributed to 2 key factors, namely, the replacement of Yolov4-tiny with Yolov7 and the expansion of noncarbohydrate source foods in the training image data set.
RESULTS
This combination significantly enhances the system's ability to identify food items, especially in scenarios with closely packed food images, thus improving accuracy. Validation results showcase the superior performance of the INMU iFood integrated V7-based system over its predecessor, V4-based, with notable improvements in protein and fat estimation. Furthermore, INMU iFood addresses limitations by offering users the option to import additional food products via a barcode scanner, thus providing access to a vast database of nutritional information through Open Food Facts. This integration ensures users can track their dietary intake effectively, with expanded access to over 3000 food items added to or updated in the Open Food Facts database covering a wide variety of dietary choices.
CONCLUSIONS
INMU iFood is a promising tool for researchers, health care professionals, and individuals seeking to monitor their dietary intake within the context of Thai cuisine and for ultimately promoting better health outcomes and facilitating nutrition-related research.
PubMed: 38774499
DOI: 10.1016/j.cdnut.2024.102154 -
BioRxiv : the Preprint Server For... May 2024Nucleoporins (nups) in the central channel of nuclear pore complexes (NPCs) form a selective barrier that suppresses the diffusion of most macromolecules while enabling...
Nucleoporins (nups) in the central channel of nuclear pore complexes (NPCs) form a selective barrier that suppresses the diffusion of most macromolecules while enabling rapid transport of nuclear transport receptors (NTRs) with bound cargos. The complex molecular interactions between nups and NTRs have been thought to underlie the gatekeeping function of the NPC. Recent studies have shown considerable variation in NPC diameter but how altering NPC diameter might impact the selective barrier properties remains unclear. Here, we build DNA nanopores with programmable diameters and nup arrangement to mimic NPCs of different diameters. We use hepatitis B virus (HBV) capsids as a model for large-size cargos. We find that Nup62 proteins form a dynamic cross-channel meshwork impermeable to HBV capsids when grafted on the interior of 60-nm wide nanopores but not in 79-nm pores, where Nup62 cluster locally. Furthermore, importing substantially changes the dynamics of Nup62 assemblies and facilitates the passage of HBV capsids through NPC mimics containing Nup62 and Nup153. Our study shows the transport channel width is critical to the permeability of nup barriers and underscores the role of NTRs in dynamically remodeling nup assemblies and mediating the nuclear entry of viruses.
PubMed: 38766144
DOI: 10.1101/2024.05.09.593438 -
Cell Stress & Chaperones Jun 2024More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated... (Review)
Review
More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated action of molecular chaperones for their folding and activation. Several heat shock protein (Hsp) molecular chaperones, including members of the Hsp27, Hsp40/70, and Hsp90 families, as well as the chaperonin complex Hsp60/10 have an established role in mitochondrial protein import and folding. The "Chaperone Code" describes the regulation of chaperone activity by dynamic post-translational modifications; however, little is known about the post-translational regulation of mitochondrial chaperones. Dissecting the regulation of chaperone function is essential for understanding their differential regulation in pathogenic conditions and the potential development of efficacious therapeutic strategies. Here, we summarize the recent literature on post-translational regulation of mitochondrial chaperones, the consequences for mitochondrial function, and potential implications for disease.
Topics: Humans; Mitochondria; Molecular Chaperones; Mitochondrial Proteins; Animals; Protein Processing, Post-Translational; Heat-Shock Proteins; Protein Folding
PubMed: 38763405
DOI: 10.1016/j.cstres.2024.05.002 -
Nature Communications May 2024The molecular system regulating cellular mechanical properties remains unexplored at single-cell resolution mainly due to a limited ability to combine mechanophenotyping...
The molecular system regulating cellular mechanical properties remains unexplored at single-cell resolution mainly due to a limited ability to combine mechanophenotyping with unbiased transcriptional screening. Here, we describe an electroporation-based lipid-bilayer assay for cell surface tension and transcriptomics (ELASTomics), a method in which oligonucleotide-labelled macromolecules are imported into cells via nanopore electroporation to assess the mechanical state of the cell surface and are enumerated by sequencing. ELASTomics can be readily integrated with existing single-cell sequencing approaches and enables the joint study of cell surface mechanics and underlying transcriptional regulation at an unprecedented resolution. We validate ELASTomics via analysis of cancer cell lines from various malignancies and show that the method can accurately identify cell types and assess cell surface tension. ELASTomics enables exploration of the relationships between cell surface tension, surface proteins, and transcripts along cell lineages differentiating from the haematopoietic progenitor cells of mice. We study the surface mechanics of cellular senescence and demonstrate that RRAD regulates cell surface tension in senescent TIG-1 cells. ELASTomics provides a unique opportunity to profile the mechanical and molecular phenotypes of single cells and can dissect the interplay among these in a range of biological contexts.
Topics: Single-Cell Analysis; Animals; Mice; Humans; Transcriptome; Cell Line, Tumor; Phenotype; Gene Expression Profiling; Cellular Senescence; Surface Tension; Electroporation; Cell Membrane
PubMed: 38760380
DOI: 10.1038/s41467-024-48088-5 -
Medicine May 2024To explore the potential mechanism of Chai Gui Zexie Decoction for non-small cell lung cancer (NSCLC) treatment using network pharmacology, bioinformatics, and molecular... (Observational Study)
Observational Study
To explore the potential mechanism of Chai Gui Zexie Decoction for non-small cell lung cancer (NSCLC) treatment using network pharmacology, bioinformatics, and molecular docking. The active ingredients of Chai Gui Zexie Decoction and the associated predicted targets were screened using the TCMSP database. NSCLC-related targets were obtained from GeneCards and OMIM. Potential action targets, which are intersecting drug-predicted targets and disease targets, were obtained from Venny 2.1. The protein-protein interaction network was constructed by importing potential action targets into the STRING database, and the core action targets and core ingredients were obtained via topological analysis. The core action targets were entered into the Metascape database, and Gene Ontology annotation analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed. Differentially expressed genes were screened using the Gene Expression Omnibus, and the key targets were obtained by validating the core action targets. The key targets were input into The Tumor IMmune Estimation Resource for immune cell infiltration analysis. Finally, the molecular docking of key targets and core ingredients was performed. We obtained 60 active ingredients, 251 drug prediction targets, and 2133 NSCLC-related targets. Meanwhile, 147 potential action targets were obtained, and 47 core action targets and 40 core ingredients were obtained via topological analysis. We detected 175 pathways related to NSCLC pharmaceutical therapy. In total, 1249 Gene Ontology items were evaluated. Additionally, 3102 differential genes were screened, and tumor protein P53, Jun proto-oncogene, interleukin-6, and mitogen-activated protein kinase 3 were identified as the key targets. The expression of these key targets in NSCLC was correlated with macrophage, CD4+ T, CD8+ T, dendritic cell, and neutrophil infiltration. The molecular docking results revealed that the core ingredients have a potent affinity for the key targets. Chai Gui Zexie Decoction might exert its therapeutic effect on NSCLC through multiple ingredients, targets, and signaling pathways.
Topics: Carcinoma, Non-Small-Cell Lung; Molecular Docking Simulation; Humans; Drugs, Chinese Herbal; Lung Neoplasms; Computational Biology; Network Pharmacology; Protein Interaction Maps; Proto-Oncogene Mas; Gene Ontology
PubMed: 38758858
DOI: 10.1097/MD.0000000000038204 -
Medicine May 2024To investigate the mechanism by which high-dose vitamin C (HVC) promotes ferroptosis in tumor cells via network pharmacology, vitamin C-related and ferroptosis-related... (Review)
Review
To investigate the mechanism by which high-dose vitamin C (HVC) promotes ferroptosis in tumor cells via network pharmacology, vitamin C-related and ferroptosis-related targets were obtained from the PharmMapper and GeneCards databases, respectively, and their common targets were compared using the Venn diagram. Common targets were imported into the STRING database for protein-protein interaction analysis, and core targets were defined. Core targets were enriched for Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways using the R language packages. A map of the core target-based interaction network and a map of the mechanism by which HVC regulates ferroptosis were constructed. A total of 238 vitamin C-related and 721 ferroptosis-related targets were identified, of which 21 targets were common to both. Furthermore, ALDOA, AHCY, LDHB, HSPA8, LGALS3, and GSTP1 were identified as core targets. GO enrichment analysis suggested that the main biological processes included the extrinsic apoptotic signaling pathway and pyruvate metabolic process. KEGG enrichment analysis suggested that HVC regulates ferroptosis mainly through the amino acid and carbohydrate metabolic pathways. The targets were validated by molecular docking. In conclusion, HVC may promote ferroptosis in tumor cells by regulating metabolic pathways, and there is a synergistic effect between HVC and type I ferroptosis inducers. Glycolysis-dependent tumors may be beneficial for HVC therapy. Our study provides a reference for further clinical studies on HVC antitumor therapy.
Topics: Ferroptosis; Humans; Molecular Docking Simulation; Ascorbic Acid; Network Pharmacology; Neoplasms; Protein Interaction Maps
PubMed: 38758839
DOI: 10.1097/MD.0000000000038189 -
Microbiology Spectrum Jun 2024We describe four cases of a novel carbapenem-resistant ST179 clone carrying the or gene together with , imported from Peru to Spain and isolated from leukemia...
UNLABELLED
We describe four cases of a novel carbapenem-resistant ST179 clone carrying the or gene together with , imported from Peru to Spain and isolated from leukemia patients. All isolates were multidrug-resistant but remained susceptible to fosfomycin, cefiderocol, and colistin. Whole-genome sequencing revealed that and were located in an IncP6 plasmid, whereas was in a chromosomal type 1 integron. This study highlights the global threat of multidrug-resistant clones and underscores the importance of monitoring and early detection of emerging resistance mechanisms to guide appropriate treatment strategies. The importation and spread of such clones emphasize the urgent need to implement strict infection control measures to prevent the dissemination of carbapenem-resistant bacteria.
IMPORTANCE
This is the first documented case of a ST179 strain carrying the blaKPC-35 gene, and it represents the first report of a co-harboring blaIMP-16 and either blaKPC-2 or blaKPC-35, which wre imported from Peru to Spain, highlighting a threat due to the capacity of spreading carbapenem-resistance via plasmid conjugation.
Topics: Pseudomonas aeruginosa; Humans; Spain; Peru; Pseudomonas Infections; Carbapenems; beta-Lactamases; Anti-Bacterial Agents; Male; Drug Resistance, Multiple, Bacterial; Plasmids; Microbial Sensitivity Tests; Bacterial Proteins; Whole Genome Sequencing; Female; Middle Aged; Adult
PubMed: 38727230
DOI: 10.1128/spectrum.00614-24