OGT-mediated AIMP2 O-GlcNAcylation promotes PARP1 overactivation in ageing-associated liver steatosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus (mouse)
SUBMITTER: Yongzhan Nie
PROVIDER: PXD027462 | JPOST Repository | Thu Jul 21 00:00:00 BST 2022
REPOSITORIES: jPOST
Dataset's files
Similar Datasets
Project description:we identified 245 down-regulated and 343 up-regulated liver proteins in aged mice. Of note, the proteins Xbp1 and Bax, which are well recognized to be involved in the regulation of ageing, were also enriched, indicating that our proteomics results are credible. Moreover，some of enriched proteins are involved in cellular processes that are widely recognized as important for aging. Livers of ageing mice exhibited changed methylation, loss of proteostasis (protein folding alteration, decreased autophagy, and increased ubiquitination), increased apoptosis, dysregulated rhythmic process, and gut dysbiosis.
2021-05-27 | PXD026294 | JPOST Repository
Project description:Increased protein misfolding and aggregation are key hallmarks of ageing and many age-related diseases. As generating and maintaining a functional proteome (proteostasis) is crucial to every cellular process, this age-related decline in proteostasis is suggested to play a primary role in the breakdown of diverse cellular subsystems during ageing. Indeed, augmented proteostasis pathways are associated with extended lifespan across different species. With the ribosome as the earliest proteostasis checkpoint, decreased protein synthesis is also a conserved mechanism that extends lifespan. Yet, it remains unclear whether ageing impacts translation after initiation. Here, we use worms and yeast to investigate how ageing influences translation elongation. We show an age-dependent increase in ribosome pausing at diverse positions in coding sequences. This pausing is conserved in both worms and yeast, particularly at Arg and polybasic regions. We further show that such pausing is associated with the age-dependent aggregation of truncated nascent proteins involved in proteostasis pathways, notably aminoacyl tRNA synthetases. Moreover, we find that impairment in clearing truncated nascent proteins is associated with decreased lifespan. These data establish elongation kinetics and co-translational quality control as critical contributors of the age-related proteostasis collapse, which may precipitate the systemic decline observed during ageing.
2021-11-09 | GSE152850 | GEO
Project description:The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular system. However, the molecular basis of proteostasis decline in vascular cells, as well as its relation to ageing, are not understood. Recent studies have indicated the associations of Nrf2 transcription factor, the critical modulator of cellular stress-response, with ageing and premature senescence. In this report, we outline the significance of protein aggregation in physiological and premature ageing of murine and human endothelial cells (ECs). Our study shows that aged donor-derived and prematurely senescent Nrf2-deficient primary human ECs, but not those overexpressing dominant-negative Nrf2, exhibit increased accumulation of protein aggregates. Such phenotype is also found in the aortas of aged mice and young Nrf2 tKO mice. Ageing-related loss of proteostasis in ECs depends on Keap1, well-known repressor of Nrf2, recently perceived as a key independent regulator of EC function. Ageing-induced deposition of protein aggregates in ECs is associated with impaired autophagy and can be counteracted by Keap1 depletion or rapamycin treatment. Our results show that Keap1:Nrf2 protein balance predominates Nrf2 transcription-dependent mechanisms in governing proteostasis and ageing in ECs.
2020-08-12 | PXD018969 | Pride
Project description:To gain in situ information on the transcriptional profile of the different zones upon ageing, we used the 10X Genomics Visium Platform and ran 5µm tissue cryosections from livers of 2 young and 2 old mice. We investigated the transcriptional events that differentiate lipid metabolism in ageing, across the different zones of the liver tissue.
2023-11-09 | E-MTAB-12809 | biostudies-arrayexpress
Project description:Krohn2011 - Cerebral amyloid-β
proteostasis regulated by membrane transport protein ABCC1
This model is described in the article:
Cerebral amyloid-β
proteostasis is regulated by the membrane transport protein
ABCC1 in mice.
Krohn M, Lange C, Hofrichter J,
Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T,
Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A,
Gsponer J, Walker LC, Pahnke J.
J. Clin. Invest. 2011 Oct; 121(10):
3924-3931
Abstract:
In Alzheimer disease (AD), the intracerebral accumulation of
amyloid-β (Aβ) peptides is a critical yet poorly understood
process. Aβ clearance via the blood-brain barrier is reduced by
approximately 30% in AD patients, but the underlying mechanisms
remain elusive. ABC transporters have been implicated in the
regulation of Aβ levels in the brain. Using a mouse model of AD
in which the animals were further genetically modified to lack
specific ABC transporters, here we have shown that the
transporter ABCC1 has an important role in cerebral Aβ
clearance and accumulation. Deficiency of ABCC1 substantially
increased cerebral Aβ levels without altering the expression of
most enzymes that would favor the production of Aβ from the Aβ
precursor protein. In contrast, activation of ABCC1 using
thiethylperazine (a drug approved by the FDA to relieve nausea
and vomiting) markedly reduced Aβ load in a mouse model of AD
expressing ABCC1 but not in such mice lacking ABCC1. Thus, by
altering the temporal aggregation profile of Aβ,
pharmacological activation of ABC transporters could impede the
neurodegenerative cascade that culminates in the dementia of
AD.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000618.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000618 | BioModels
Project description:Maintaining proteostasis is key to resisting stress and to promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions in proteostasis contribute stem cell aging is largely unexplored. We determined that ex vivo cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.
2021-07-11 | GSE179413 | GEO
Project description:Maintaining proteostasis is key to resisting stress and to promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions in proteostasis contribute stem cell aging is largely unexplored. We determined that ex vivo cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.
2021-07-11 | GSE179412 | GEO
Project description:Background Muscle ageing contributes to both loss of functional autonomy and increased morbidity. Muscle atrophy accelerates after 50 years of age, but the mechanisms involved are complex and likely result from the alteration of a variety of interrelated functions. In order to better understand the molecular mechanisms underlying muscle chronological ageing in human, we have undertaken a top-down differential proteomic approach to identify novel biomarkers after the fifth decade of age. Results Muscle samples were compared between adult (56 years) and old (78 years) post-menopausal women. In addition to total muscle extracts, low-ionic strength extracts were investigated to remove high abundance myofibrillar proteins and improve the detection of low abundance proteins. Two-dimensional gel electrophoreses with overlapping IPGs were used to improve the separation of muscle proteins. Overall, 1919 protein spots were matched between all individuals, 95 were differentially expressed and identified by mass spectrometry, and they corresponded to 67 different proteins. Our results suggested important modifications in cytosolic, mitochondrial and lipid energy metabolism, which may relate to dysfunctions in old muscle force generation. A fraction of the differentially expressed proteins were linked to the sarcomere and cytoskeleton (myosin light-chains, troponin T, ankyrin repeat domain-containing protein-2, vinculin, four and a half LIM domain protein-3), which may account for alterations in contractile properties. In line with muscle contraction, we also identified proteins related to calcium signal transduction (calsequestrin-1, sarcalumenin, myozenin-1, annexins). Muscle ageing was further characterized by the differential regulation of several proteins implicated in cytoprotection (catalase, peroxiredoxins), ion homeostasis (carbonic anhydrases, selenium-binding protein 1) and detoxification (aldo-keto reductases, aldehyde dehydrogenases). Notably, many of the differentially expressed proteins were central for proteostasis, including heat shock proteins and proteins involved in proteolysis (valosin-containing protein, proteasome subunit beta type-4, mitochondrial elongation factor-Tu). Conclusions This study describes the most extensive proteomic analysis of muscle ageing in humans, and identified 34 new potential biomarkers. None of them were previously recognized as differentially expressed in old muscles, and each may represent a novel starting point to elucidate the mechanisms of muscle chronological ageing in humans.
2015-02-19 | PXD001527 | Pride
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one third of the global population. Understanding metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific
ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated
acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
2023-12-12 | MSV000093653 | MassIVE
Project description:Purpose: Conditional MOF deletion in mouse livers resulted in acute hepatic necrosis. The goal of this study was to identify transcriptomic changes in the livers of MOF-depeleted mice livers compared to WT. Methods: Transcriptomic profiles of MOF∆ and WT mouse livers were generated in triplicate. Sequenced reads were quality filtered using Trimmomatic. Quality reads were aligned to the mouse genome using TopHat2. Reads were counted using htseq-count and differentially expressed transcripts were identified using DESeq. Results: 1408 differentially expressed genes were identified between MOF∆ and WT livers. 774 genes were down-regulated in MOF∆ and primarilly associated with metabolic pathways. Branched chain amino acid and fatty acid metabolic pathways, which are deregulated in non-alcoholic fattly liver disease (NAFLD) prgression were down-regulated. 664 genes were upregulated and associated with increased proliferation. Conclusions: These data show that MOF is required for maintaining proper metabolic function in the liver and deregulation of MOF may be involved in progression of NAFLD.
2018-01-31 | GSE106369 | GEO