Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Iron accumulation and changes of cellular organelles in WDR45 mutant fibroblasts

ABSTRACT: Iron overload in the brain, defined as excess stores of iron, is known to be related to neurological disorder. Among neurodegeneration with brain iron accumulation, we reported a specific point mutation, 977-1G>A in WDR45, showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on other organelles, including lipid droplets, mitochondria, and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria, and increased lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. The majority of iron accumulation occurred in the lysosomal vesicles, according to correlative light and electron microscopy (CLEM). These changes were related to defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed significant changes in lipid metabolism, mitochondrial function, and autophagy-related genes. Those data suggested that functional and structural changes caused impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, due to iron overload.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184520 | GEO | 2021/11/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Iron accumulation and changes of cellular organelles in WDR45 mutant fibroblasts

Project description:Iron accumulation and changes of cellular organelles in WDR45 mutant fibroblasts

| PRJNA764903 | ENA

Iron limitation restores autophagy and increases lifespan in the yeast model of Niemann-Pick type C1

Project description:Niemann Pick Type C1 (NPC1) is an endolysosomal transmembrane protein involved in the export of cholesterol and sphingolipids to other cellular compartments such as the endoplasmic reticulum and plasma membrane. NPC1 loss of function is the major cause of NPC disease, a rare lysosomal storage disorder characterized by an abnormal accumulation of lipids in the late endosomal/lysosomal network, mitochondrial dysfunction, and impaired autophagy. NPC phenotypes are conserved in yeast lacking Ncr1, orthologue of human NPC1, leading to premature ageing. Herein, we performed a phosphoproteomic analysis to investigate the effect of Ncr1 loss on cellular functions mediated by the yeast lysosome-like vacuoles. Our results revealed changes in vacuolar membrane proteins that are associated mostly with vesicle biology (fusion, transport, organization), autophagy and ion homeostasis, including iron, manganese, and calcium. Consistently, the Cytoplasm to vacuole targeting (Cvt) pathway was increased in ncr1∆ cells and autophagy was compromised despite TORC1 inhibition. Moreover, ncr1∆ cells exhibited iron overload mediated by the low‑iron sensing transcription factor Aft1. Iron deprivation restored the autophagic flux of ncr1∆ cells and increased its chronological lifespan and oxidative stress resistance. These results implicate iron overload on autophagy impairment, oxidative stress sensitivity and cell death in the yeast model of NPC1.

2023-03-31 | PXD039881 | Pride

Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury

Project description:Iron overload, characterized by accumulation of iron in tissues, induces a multiorgan toxicity whose mechanisms are not fully understood. Using cultured cell lines, Caenorhabditis elegans, and mice, we found that ferroptosis occurs in the context of iron-overload-mediated damage. Exogenous oleic acid protected against iron-overload-toxicity in cell culture and Caenorhabditis elegans by suppressing ferroptosis. In mice, oleic acid protected against FAC-induced liver lipid peroxidation and damage. Oleic acid changed the cellular lipid composition, characterized by decreased levels of polyunsaturated fatty acyl phospholipids and decreased levels of ether-linked phospholipids. The protective effect of oleic acid in cells was attenuated by GW6471 (a PPAR- antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR- functional homologue). These results highlight ferroptosis as a driver of iron-overload-mediated damage, which is inhibited by oleic acid. This monounsaturated fatty acid represents a potential therapeutic approach to mitigating organ damage in iron overload individuals.

2023-10-02 | GSE243891 | GEO

Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells

Project description:Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used a mouse model of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy, and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes, and ceramides. The proteolytic enzyme cathepsin D had impaired maturation. A large proportion of lysosomes were galectin-3 positive, suggesting cytotoxic lysosomal membrane permeabilization. RNA sequencing was performed and did not show evidence of upregulation of CLEAR network genes, suggesting that the lysosomal accumulation was due to decreased lysosomal turnover and not increased lysosomal biogenesis. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely owing to iron-induced lipid peroxides that can inhibit lysosomal enzymes.

2023-07-13 | GSE237309 | GEO

Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells

Project description:Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration(AMD), the leading cause of blindness in the elderly, with retinal pigment epithelial (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured iPS-RPE cells increased lysosomal abundance, impaired proteolysis, and reduced the activity of a subset of lysosomal enzymes,including lysosomal acid lipase and acid sphingomyelinase. In a murine model of systemiciron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy, and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes, and ceramides. The proteolytic enzyme cathepsin D had impaired maturation. A large proportion oflysosomes were galectin-3 positive, suggesting cytotoxic lysosomal membrane permeabilization (LMP). Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes.

2023-07-19 | PXD043613 | Pride

Effects of iron overload on gene expression in the cardiac and skeletal muscle of mice

Project description:Hereditary Hemochromatosis (HH) is an autosomal recessive disorder characterized by an abnormally low expression or functional derangement of the iron regulatory hormone hepcidin. The absorption of dietary iron is disproportionate in these patients, leading to iron deposition in several tissues and consequent damage of organs including liver, heart, and pancreas. Late complications in absence of diagnosis and treatment include cirrhosis, hepatocellular carcinoma, cardiomyopathy and diabetes. Unfortunately, iron overload appears also as an acquired complication. This is the case of a variety of anemias (thalassemias, myelodysplastic syndromes, hemoglobinopathies, etc.) in which compensating mechanisms increase iron absorption. Another cause of iron overload in these patients are the repeated transfusional treatments they receive. It follows that iron overload is a common clinical problem. Therefore, we investigated the effects of iron overload on gene expression in skeletal muscle and heart using microarray technology. Genes with up-regulated expression after iron overload in both skeletal and heart muscle included angiopoietin-like 4, pyruvate dehydrogenase kinase 4 and calgranulin A and B. The expression of transferrin receptor, heat shock protein 1B and DnaJ homolog B1 were down-regulated by iron in both muscle types. Two potential hepcidin regulatory genes, hemojuvelin and neogenin, showed no clear change in expression after iron overload. Concluding, microarray analysis revealed iron-induced changes in the expression of several genes involved in the regulation of glucose and lipid metabolism, transcription and cellular stress responses. These may represent novel connections between iron overload and pathological manifestations of HH such as cardiomyopathy and diabetes. Keywords: iron induced stress response

2007-11-30 | GSE9726 | GEO

Lipid droplet proteomics of THP1 macrophages infected with Mycobacterium tuberculosis

Project description:Growing evidence suggests the importance of lipid metabolism in pathogenesis of tuberculosis. Neutral lipids form the majority of lipids in caseous granulomas characteristic of tuberculosis. Macrophage lipid droplets form the store house of these lipids, yet infection induced changes in the proteome of these dynamic organelles remains elusive. Here we employed quantitative proteomics to identify alterations induced upon infection with live Mycobacterium tuberculosis in comparison with heat killed bacilli and uninfected macrophages. Association of specific proteins coupled with lysosomal function was found to be increased upon infection with live M. tuberculosis. Biochemical and microscopy based evidence validated the enrichment of the small GTPase Arl8b, the guanine nucleotide effector LAMTOR1, and the scavenger receptor SCARB2 on lipid droplets during live Mtb infection. We validated the localization of Arl8b on lipid droplets using super-resolution microscopy. Increased abundance of these lysosomal proteins on lipid droplets upon infection with live Mtb suggests active manipulation of the host lipid droplets by the pathogen. Furthermore, depletion of lipid droplets upon stable knockdown of diacylglycerol O-acyltransferase led to reduction in lysosomal acidification of infected cells, suggesting an active role of lipid droplets in lysosomal function during infection.

2019-11-14 | PXD008950 | Pride

Iron overload alleviates pathologies in FSHD mice through suppression of ferroptosis pathway

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in loss of muscle mass and function. However, the mechanism through which DUX4 exerts its toxicity remains unclear. Here, we observed abnormal iron accumulation in the muscles of patients with FSHD and in muscle-specific DUX4 expressing (DUX4-Tg) mice. Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve or exacerbate FSHD pathology in DUX4-Tg mice. Unexpectedly, however, iron overload caused by a high-iron diet or intravenous iron administration resulted in remarkable improvement in muscle strength, running performance, and locomotor activity in DUX4-Tg mice. Mechanistically, iron overload suppresses DUX4-activated ferroptosis, an iron-induced cell death pathway that involves increased lipid peroxidation. Notably, muscle-specific DUX4 expression led to retinal vasculopathy, a part of FSHD pathology, which was markedly prevented by iron overload. Furthermore, high-throughput compound screening of the ferroptosis pathway has identified drug candidates that attenuate DUX4 toxicity. Taken together, our findings demonstrate that DUX4-provoked toxicity is involved in the activation of the ferroptosis pathway in muscles and that iron overload could be a promising and readily available therapeutic option for FSHD.

2025-03-31 | GSE261617 | GEO

Transcription profiling of liver from wild type and Hfe-/- mice with hereditary hemochromatosis subjected to dietary iron overload and treatment with nifedipine to reverse iron overload

Project description:Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues leading to eventual organ failure. We have discovered a novel mechanism to reverse iron overload by pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Additional functions in iron handling in the kidney and liver are less well understood. We show that the L- type calcium-channel blocker nifedipine increases DMT-1 mediated cellular iron transport 10-to 100-fold at concentrations between 1-100 uM. Mechanistically, nifedipine causes this effect by prolongation of the activity of DMT-1 to transport iron. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload, and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium-channel blockers emerges a novel pharmacological concept to treat iron overload disorders.<br> <br> In this experiment mice were subjected to dietary iron overload before being treated with nifedipine at 5 ug/g bodyweight, or mock treated with the same volume of solvent.

2007-03-01 | E-MEXP-982 | biostudies-arrayexpress

Proteomics coupled transcriptomics reveals lipopolysaccharide inhibiting peroxisome proliferator-activated receptors signalling pathway to reduce lipid droplets accumulation in mouse liver

Project description:Lipid droplets (LDs) are multifunctional organelles consisting of a central compartment of non-polar lipids shielded from the cytoplasm by a phospholipid monolayer. The excessive accumulation of lipid droplets in cells is closely related to the development and progression of many diseases in humans and animals, such as liver-related and cardiovascular diseases. Thus, regulating the LDs size and abundance is necessary to maintain metabolic homeostasis. In this study, we found that LPS stimulation reduced the LDs content in the mouse liver. We tried to explain the possible molecular mechanisms at the broad protein and mRNA levels, finding that inhibition of the peroxisome proliferator-activated receptors (PPAR) signalling pathway by LPS may be a critical factor in reducing LDs content.

2023-02-02 | GSE224012 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data