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Plant Direct Jun 2024Chloroplasts play a vital role in plant growth and development, which are the main sites of photosynthesis and the production of hormones and metabolites. Despite their...
Chloroplasts play a vital role in plant growth and development, which are the main sites of photosynthesis and the production of hormones and metabolites. Despite their significance, the regulatory mechanisms governing chloroplast development remain unclear. In our investigation, we identified a rice mutant with defective chloroplasts in rice ( L.), named albino lethal 13 (), which displayed a distinct albino phenotype in leaves, ultimately resulting in seedling lethality. Molecular cloning revealed that encodes a novel rice protein with no homologous gene or known conserved domain. This gene was located in the chloroplast and exhibited constitutive expression in various tissues, particularly in green tissues and regions of active cell growth. Our study's findings reveal that RNAi-mediated knockdown of led to a pronounced albino phenotype, reduced chlorophyll and carotenoid contents, a vesicle chloroplast structure, and a decrease in the expression of chloroplast-associated genes. Consequently, the pollen fertility and seed setting rate were lower compared with the wild type. In contrast, the overexpression of resulted in an increased photosynthetic rate, a higher total grain number per panicle, and enhanced levels of indole-3-acetic acid (IAA) in the roots and gibberellin A3 (GA3) in the shoot. These outcomes provide new insights on the role of in regulating chloroplast development in rice.
PubMed: 38903415
DOI: 10.1002/pld3.610 -
Nature Communications Jun 2024Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial...
Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.
Topics: Dyrk Kinases; Protein-Tyrosine Kinases; Protein Serine-Threonine Kinases; Mitochondria; Mitochondrial Precursor Protein Import Complex Proteins; Signal Transduction; Humans; Mitochondrial Membrane Transport Proteins; Phosphorylation; Protein Transport; HEK293 Cells; HeLa Cells; Mitochondrial Proteins
PubMed: 38902238
DOI: 10.1038/s41467-024-49611-4 -
PloS One 2024Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and...
Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and provide new targets to manage hair loss disorders. The Mitochondrial Pyruvate Carrier (MPC) imports pyruvate, produced via glycolysis, into the mitochondria, fuelling the TCA cycle. Previous work has shown that MPC inhibition promotes lactate generation, which activates murine epithelial hair follicle stem cells (eHFSCs). However, by pharmacologically targeting the MPC in short-term human hair follicle ex vivo organ culture experiments using UK-5099, we induced metabolic stress-responsive proliferative arrest throughout the human hair follicle epithelium, including within Keratin 15+ eHFSCs. Through transcriptomics, MPC inhibition was shown to promote a gene expression signature indicative of disrupted FGF, IGF, TGFβ and WNT signalling, mitochondrial dysfunction, and activation of the integrated stress response (ISR), which can arrest cell cycle progression. The ISR, mediated by the transcription factor ATF4, is activated by stressors including amino acid deprivation and ER stress, consistent with MPC inhibition within our model. Using RNAScope, we confirmed the upregulation of both ATF4 and the highly upregulated ATF4-target gene ADM2 on human hair follicle tissue sections in situ. Moreover, treatment with the ISR inhibitor ISRIB attenuated both the upregulation of ADM2 and the proliferative block imposed via MPC inhibition. Together, this work reveals how the human hair follicle, as a complex and metabolically active human tissue system, can dynamically adapt to metabolic stress.
Topics: Humans; Hair Follicle; Activating Transcription Factor 4; Stress, Physiological; Cell Proliferation; Mitochondria
PubMed: 38900734
DOI: 10.1371/journal.pone.0303742 -
ELife Jun 2024Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria...
Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
Topics: Saccharomyces cerevisiae; Mitochondria; Humans; Protein Transport; Protein Folding; Protein Serine-Threonine Kinases; Saccharomyces cerevisiae Proteins; Glucose
PubMed: 38900507
DOI: 10.7554/eLife.87518 -
Current Microbiology Jun 2024Pyruvate (Pyr) is the end product of the glycolysis pathway. Pyr is also renewable and is further metabolized to produce formate, which is the precursor of H, via...
Pyruvate (Pyr) is the end product of the glycolysis pathway. Pyr is also renewable and is further metabolized to produce formate, which is the precursor of H, via pyruvate formate lyase (PFL) under anaerobic conditions. The formate is excluded and re-imported via the formate channel and is then converted to H via the formate hydrogenlyase (FHL) complex. In H producing marine vibrios, such as Vibrio tritonius and Vibrio porteresiae in the Porteresiae clade of the family Vibrionaceae, apparent but inefficient H production from Pyr has been observed. To elucidate the molecular mechanism of why this inefficient H production is observed in Pry-metabolized marine vibrio cells and how glycolysis affects those H productions of marine vibrios, the "Core Transcriptome" approach to find common gene expressions of those two major H producing Vibrio species in Pyr metabolism was first applied. In the Pyr-metabolized vibrio cells, genes for the "Phosphoenolpyruvate (PEP)-Pyruvate-Oxalate (PPO)" node, due to energy saving, and PhoB-, RhaR-, and DeoR-regulons were regulated. Interestingly, a gene responsible for oxalate/formate family antiporter was up-regulated in Pyr-metabolized cells compared to those of Glc-metabolized cells, which provides new insights into the uses of alternative formate exclusion mechanics due to energy deficiencies in Pyr-metabolized marine vibrios cells. We further discuss the contribution of the Embden-Meyerhof-Parnas (EMP) pathway to efficient H production in marine vibrios.
Topics: Hydrogen; Vibrio; Transcriptome; Glycolysis; Pyruvic Acid; Bacterial Proteins; Seawater; Gene Expression Regulation, Bacterial; Aquatic Organisms
PubMed: 38896159
DOI: 10.1007/s00284-024-03764-z -
BioRxiv : the Preprint Server For... Jun 2024In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that...
In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
PubMed: 38895386
DOI: 10.1101/2024.06.04.597442 -
Frontiers in Aging Neuroscience 2024Now, there are no sensitive biomarkers for improving Alzheimer's disease (AD) and comorbid Parkinson's disease (PD). The aim of the present study was to analyze...
BACKGROUND
Now, there are no sensitive biomarkers for improving Alzheimer's disease (AD) and comorbid Parkinson's disease (PD). The aim of the present study was to analyze differentially expressed genes (DEGs) in brain tissue from AD and PD patients via bioinformatics analysis, as well as to explore precise diagnostic and therapeutic targets for AD and comorbid PD.
METHODS
GFE122063 and GSE7621 data sets from GEO in NCBI, were used to screen differentially expressed genes (DEGs) for AD and PD, and identify the intersected genes, respectively. Intersected genes were analyzed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, STRING site and Cytoscape were used to construct a protein-protein interaction (PPI) network, CytoNCA algorithm to analyze and evaluate centrality, Mcode plug-in to analyze module, and Cytohubba to screen key genes. Combined GO-KEGG enrichment analysis with Cytoscape algorithm to screen the key gene in AD complicated with PD. Then, the DEGs for AD and PD were imported into the Association Map (CMap) online platform to screen out the top 10 small molecule drugs, and using molecular docking techniques to evaluate the interactions between small molecule drugs and key genes receptors.
RESULTS
In total, 231 upregulated genes and 300 downregulated genes were identified. GO analysis revealed that the DEGs were highly enriched in signal transduction, and KEGG analysis revealed that the DEGs were associated with the MAPK and PI3K-Akt signaling pathways. Epidermal growth factor receptor (EGFR) was identified as a potential receptor gene in AD and comorbid PD. EGFR was upregulated in both AD and PD, and the proteins that interact with EGFR were enriched in the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Semagacestat was identified as a drug with therapeutic potential for treating AD complicated with PD. There was a high binding affinity between semagacestat and EGFR, with seven hydrogen bonds and one hydrophobic bond.
DISCUSSION
Semagacestat may improve the health of patients with AD complicated with PD through the regulation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways by EGFR, providing evidence supporting the structural modification of semagacestat to develop a more effective drug for treating AD complicated with PD.
PubMed: 38894850
DOI: 10.3389/fnagi.2024.1411320 -
Nutrients May 2024Blood selenium (Se) concentrations differ substantially by population and could be influenced by genetic variants, increasing Se deficiency-related diseases. We...
Blood selenium (Se) concentrations differ substantially by population and could be influenced by genetic variants, increasing Se deficiency-related diseases. We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with serum Se deficiency in 382 adults with admixed ancestry. Genotyping arrays were combined to yield 90,937 SNPs. R packages were applied to quality control and imputation. We also performed the ancestral proportion analysis. The Search Tool for the Retrieval of Interacting Genes was used to interrogate known protein-protein interaction networks (PPIs). Our ancestral proportion analysis estimated 71% of the genome was from Caucasians, 22% was from Africans, and 8% was from East Asians. We identified the SNP rs1561573 in the TraB domain containing 2B (), rs425664 in MAF bZIP transcription factor (), rs10444656 in spermatogenesis-associated 13 (), and rs6592284 in heat shock protein nuclear import factor () genes. The PPI analysis showed functional associations of Se deficiency, thyroid hormone metabolism, NRF2-ARE and the Wnt pathway, and heat stress. Our findings show evidence of a genetic association between Se deficiency and metabolic pathways indirectly linked to Se regulation, reinforcing the complex relationship between Se intake and the endogenous factors affecting the Se requirements for optimal health.
Topics: Humans; Selenium; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Male; Female; Adult; Brazil; Middle Aged; Genetic Predisposition to Disease; White People; Genotype; Protein Interaction Maps
PubMed: 38892560
DOI: 10.3390/nu16111627 -
International Journal of Molecular... May 2024Skeletal muscle grows in response to a combination of genetic and environmental factors, and its growth and development influence the quality of pork. Elucidating the...
Skeletal muscle grows in response to a combination of genetic and environmental factors, and its growth and development influence the quality of pork. Elucidating the molecular mechanisms regulating the growth and development of skeletal muscle is of great significance to both animal husbandry and farm management. The is an excellent pig breed based on the original , importing the genes of the for meat traits, and cultivated through years of scientific selection and breeding. In this study, full-length transcriptome sequencing was performed on three growth stages of , aiming to study the developmental changes in at different developmental stages at the molecular level and to screen the key genes affecting the growth of skeletal muscle in . We performed an enrichment analysis of genes showing differential expression and constructed a protein-protein interaction network with the aim of identifying core genes involved in the development of . Notably, genes such as , , , and may be potential regulators of muscle development in . Our results contribute to the understanding of the molecular mechanisms of skeletal muscle development in this pig breed, which will facilitate molecular breeding efforts and the development of pig breeds to meet the needs of the livestock industry.
Topics: Animals; Muscle, Skeletal; Swine; Gene Expression Profiling; Transcriptome; Gene Expression Regulation, Developmental; Muscle Development; Breeding; Protein Interaction Maps
PubMed: 38892283
DOI: 10.3390/ijms25116095 -
Liver International : Official Journal... Jun 2024Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a... (Review)
Review
Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a prosthetic group for oxygen-carrying proteins and enzymes involved in oxidation/reduction and electron transport reactions. Heme is essential for the function of numerous hemoproteins and has numerous other roles in the biochemistry of life. In mammals, heme is synthesised from glycine, succinyl-CoA, and ferrous iron in a series of eight steps. The first and normally rate-controlling step is catalysed by 5-aminolevulinate synthase (ALAS), which has two forms: ALAS1 is the housekeeping form with highly variable expression, depending upon the supply of the end-product heme, which acts to repress its activity; ALAS2 is the erythroid form, which is regulated chiefly by the adequacy of iron for erythroid haemoglobin synthesis. Abnormalities in the several enzymes of the heme synthetic pathway, most of which are inherited partial enzyme deficiencies, give rise to rare diseases called porphyrias. The existence and role of heme importers and exporters in mammals have been debated. Recent evidence established the presence of heme transporters. Such transporters are important for the transfer of heme from mitochondria, where the penultimate and ultimate steps of heme synthesis occur, and for the transfer of heme from cytoplasm to other cellular organelles. Several chaperones of heme and iron are known and important for cell health. Heme and iron, although promoters of oxidative stress and potentially toxic, are essential cofactors for cellular energy production and oxygenation.
PubMed: 38888238
DOI: 10.1111/liv.15965