E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 2, 2025

Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate and regulation of epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model primary cells, identify transcription factor E4F1 key coordinator AcetylCoenzyme A (AcCoA) production by dehydrogenase complex (PDC) its utilization co-factor Elongator acetylate tRNAs at wobble position uridine 34 (U ). E4F1-mediated direct transcriptional Dlat Elp3 , two genes encoding subunits PDC complex, respectively, ensures proper translation fidelity survival in central nervous system (CNS) embryonic Furthermore, analysis PDH-deficient cells highlight crosstalk linking ELP3 expression is perturbed LS patients.

Язык: Английский

---

eIF4F-mediated Dysregulation of mRNA Translation in Cancer

RNA, Год журнала: 2025, Номер unknown, С. rna.080340.124 - rna.080340.124

Опубликована: Янв. 14, 2025

Messenger RNA (mRNA) translational control plays a pivotal role in regulating cellular proteostasis under physiological and pathological conditions. Dysregulated mRNA translation is pervasive cancer, which protein synthesis elevated to support accelerated cell growth proliferation. Consequently, targeting the machinery has emerged as therapeutic strategy treat cancer. In this perspective, we summarize current knowledge of dysregulation with emphasis on eukaryotic initiation factor 4F (eIF4F) complex. We outline recent endeavors apply develop novel treatment strategies combat

Язык: Английский

---

Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle

RNA Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 21, 2025

Gene expression involves a series of consequential processes, beginning with mRNA synthesis and culminating in translation. Traditionally studied as linear sequence events, recent findings challenge this perspective, revealing coupling mechanisms that coordinate key steps gene expression, even when spatially temporally distant. In review, we focus on translation, the final stage examine its stages metabolism: synthesis, processing, export, decay. For each these provide an overview known instances Furthermore, discuss role high-throughput technologies uncovering intricate interactions genome-wide scale. Finally, highlight challenges propose future directions to advance our understanding how orchestrate robust adaptable programs.

Язык: Английский

---

Half a Century of Progress: The Evolution of Wheat Germ-Based In Vitro Translation into a Versatile Protein Production Method

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3577 - 3577

Опубликована: Апрель 10, 2025

The first demonstration of wheat germ extract (WGE)-based in vitro translation synthesising a protein from exogenously introduced messenger ribonucleic acid (mRNA) was published approximately fifty years ago. Since then, there have been numerous crucial improvements to the WGE-based translation, resulting significant increase yield and development high-throughput protein-producing platforms. These developments transformed original setup into versatile eukaryotic production method with broad applications. present review explores theoretical background implemented modifications brings panel examples for WGE applications studies synthesis challenging-to-produce proteins such as complexes, extracellular proteins, membrane proteins. It also highlights unique advantages an open system radioactively labelled illustrated by publications using meet demands these studies. This aims orientate readers finding most appropriate arrangement their specific needs demonstrate that deeper understanding will help them make further adjustments reaction conditions difficult-to-express

Язык: Английский

---

CircRNAs in Colorectal Cancer: Unveiling Their Roles and Exploring Therapeutic Potential

Biochemical Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Язык: Английский

---

Regulation of gene expression through protein-metabolite interactions

npj Metabolic Health and Disease, Год журнала: 2025, Номер 3(1)

Опубликована: Март 4, 2025

Organisms have to adapt changes in their environment. Cellular adaptation requires sensing, signalling and ultimately the activation of cellular programs. Metabolites are environmental signals that sensed by proteins, such as metabolic enzymes, protein kinases nuclear receptors. Recent studies discovered novel metabolite sensors function gene regulatory proteins chromatin associated factors or RNA binding proteins. Due regulating expression, metabolite-induced allosteric control these facilitates a crosstalk between metabolism expression. Here we discuss direct processes metabolites recent progresses expand our abilities systematically characterize metabolite-protein interaction networks. Obtaining profound map networks is great interest for aiding disease treatment drug target identification.

Язык: Английский

---

Metabolism Meets Translation: Dietary and Metabolic Influences on tRNA Modifications and Codon Biased Translation

Wiley Interdisciplinary Reviews - RNA, Год журнала: 2025, Номер 16(2)

Опубликована: Март 1, 2025

ABSTRACT Transfer RNA (tRNA) is not merely a passive carrier of amino acids, but an active regulator mRNA translation controlling codon bias and optimality. The synthesis various tRNA modifications regulated by many “writer” enzymes, which utilize substrates from metabolic pathways or dietary sources. Metabolic bioenergetic pathways, such as one‐carbon (1C) metabolism the tricarboxylic acid (TCA) cycle produce essential for synthesis, S‐Adenosyl methionine (SAM), sulfur species, α‐ketoglutarate (α‐KG). activity these can directly impact decoding via regulating levels. In this review, we discuss complex interactions between diet, metabolism, modifications, translation. We how nutrient availability, bioenergetics, intermediates modulate modification landscape to fine‐tune protein synthesis. Moreover, highlight dysregulation metabolic‐tRNA contributes disease pathogenesis, including cancer, disorders, neurodegenerative diseases. also new emerging field GlycoRNA biology drawing parallels glycobiology diseases guide future directions in area. Throughout our discussion, links specific their metabolic/dietary precursors, diseases, emphasizing importance metabolism‐centric view understanding pathologies. Future research should focus on uncovering interplay cellular contexts. Addressing gaps will into novel interventions.

Язык: Английский

---

Unveiling the functional heterogeneity of endogenous tissue extracellular vesicles in skeletal muscle through multi-omics

Chemical Engineering Journal, Год журнала: 2025, Номер unknown, С. 162679 - 162679

Опубликована: Апрель 1, 2025

Язык: Английский

---

Identifying Aberrant 1CM-Related Pathways by Multi-Omics Analysis and Validating Tumor Inhibitory Effect of One-Carbon Donor Betaine in Gastric Cancer

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3841 - 3841

Опубликована: Апрель 18, 2025

Metabolic reprogramming, a well-established hallmark of gastric carcinogenesis, has been implicated in driving tumor progression. Nevertheless, the precise mechanisms through which these metabolic alterations orchestrate cancer (GC) pathogenesis remain incompletely elucidated. We conducted metabolomic analyses plasma samples obtained from 334 patients with GC and healthy individuals to identify differential metabolites pathways. Transcriptome sequencing was on six pairs tissues, joint analysis transcriptome metabolome performed. Single-cell data were acquired co-analyzed metabolomics investigate abnormalities at single-cell level. Finally, four representative selected using Random Forest subjected cellular experiments elucidate exert their effects. Metabolomic revealed that serine glycine metabolism, glycolysis, glutamate metabolism significantly altered GC, suggesting one-carbon (1CM)-related pathways are aberrantly activated. A combined transcriptome, indicated related oxidative phosphorylation, nucleotide amino acid epithelial cells GC. Cellular demonstrated donor metabolite betaine could inhibit activity, invasion, migration while activating phosphorylation AMPKα. In conclusion, 1CM-related pathway play significant roles influences warrant further investigation.

Язык: Английский

---

Combination of gallium citrate and levofloxacin induces a distinct metabolome profile and enhances growth inhibition of multidrug-resistant Mycobacterium tuberculosis compared to linezolid

Frontiers in Microbiology, Год журнала: 2024, Номер 15

Опубликована: Ноя. 29, 2024

Introduction Tuberculosis (TB) treatment typically involves a tailored combination of four antibiotics based on the drug resistance profile infecting strain. The increasing Mycobacterium tuberculosis ( Mtb ) requires development novel to ensure effective regimens. Gallium (Ga) is being explored as repurposed against TB due its ability inhibit growth and disrupt iron metabolism. Given potential interactions between Ga established antibiotics, we investigated how with levofloxacin (Lfx) or linezolid (Lzd) affects metabolome multidrug-resistant (MDR) clinical Methods was cultured using BACTEC 960 system concentrations ranging from 125 1,000 μM 250 500 combined 0.125 mg/L Lfx Lzd. For analysis, antibacterials were used at that inhibited bacteria without causing cell death. Metabolites extracted cells analyzed chromatography-mass spectrometry. Results MDR strain exhibited dose-dependent response Ga. Notably, enhancement in inhibition statistically significant for Ga/Lfx compared alone, while no such significance observed Ga/Lzd. Moreover, exposure Ga/Lzd resulted distinct metabolite profiles. increased level aconitate, fumarate, glucose cells, suggesting iron-dependent aconitase fumarate hydratase, well disruption pentose phosphate pathway. levels glucose, succinic acid, citric hexadecanoic acid followed similar pattern exposed but different trends Discussion In presence Lfx, changes induced by are more pronounced those nucleic acids transcription, which may enhance Ga-dependent preventing metabolic redirection use bypass enzymes.

Язык: Английский

---