Iron accumulation and changes of cellular organelles in WDR45 mutant fibroblasts
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ABSTRACT:
PROVIDER: PRJNA764903 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15992515_1.fastq.gz | Fastqsanger.gz | |||
| SRR15992515_2.fastq.gz | Fastqsanger.gz | |||
| SRR15992516_1.fastq.gz | Fastqsanger.gz | |||
| SRR15992516_2.fastq.gz | Fastqsanger.gz | |||
| SRR15992517_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-11-17 | GSE184520 | GEO
Project description:Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (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 cellular 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 numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.
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Project description:We found histological evidence for increased abundance of iron accumulating cells in association with fibrotic lung, kidney, and heart diseases in mice and humans. We showed that inducing iron accumulation by intratracheal iron delivery in mice is a potent inducer of inflammation, cellular senescence, and fibrosis. The aim of this study has been to understand the single cell dynamics of iron accumulation and the mechanics that link it to in vivo senescence and to fibrogenesis. To get deeper insight into how different cell types respond to iron accumulation, we performed single nuclei RNA sequencing (snRNA-seq) of lungs from mice which received a single intratracheal dose of iron 2 or 6 days prior to analysis, or PBS 6days prior to analysis (control).
2023-08-18 | E-MTAB-13032 | biostudies-arrayexpress
Project description:The Endoplasmic Reticulum–Mitochondria Encounter Structure (ERMES) is a protein complex that tethers the two organelles and creates the physical basis for communication between them. ERMES functions in lipid and calcium exchange between the ER and mitochondria, mitochondrial protein import and maintenance of mitochondrial morphology and genome. Here we report that ERMES is also required for iron homeostasis. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of ERMES known roles in calcium regulation, phospholipid biosynthesis or mitochondrial biology. A mutation in the vacuolar protein sorting 13 (VPS13) gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Our study reveals that proper communication between the ER and mitochondria is required for appropriate maintenance of cellular iron levels.
2017-06-20 | GSE99499 | GEO
Project description:Iron accumulation in microglia has been observed in Alzheimer’s disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms including neuroinflammation. To study the interaction between iron accumulation and inflammation, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with an increasing concentration of iron, in combination with inflammatory stimuli such as interferon gamma and amyloid β, and performed RNA sequencing.
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Project description:Aerobic Escherichia coli growth at restricted iron concentrations (≤ 1.75 ± 0.04 mM) is characterized by lower biomass yield, higher acetate accumulation, and higher activation of the siderophore iron-acquisition systems. Although iron homeostasis in E. coli has been studied intensively, these studies focused only on understanding the regulation of the iron import systems and the iron-requiring enzymes. In this study, the effect of iron availability on the energy metabolism of E. coli was investigated. It was established that aerobic cultures growing at limiting iron conditions showed lower ATP yield per glucose, lower growth rate, and lower TCA cycle activity and respiration, and at the same time increased glucose consumption, acetate and pyruvate accumulation, practically mimicking microaerobic growth. However, at excess iron, independently of oxygen availability, the cultures showed high cellular energetics (5.8 ATP/mol of glucose) by using pathways requiring iron-rich complex proteins found in the TCA cycle and respiration chain. At conditions of iron excess, some iron requiring terminal reductases of the respiratory chain, that were supposed to be anaerobic, were used by the E. coli, when in aerobic conditions, to keep high respiration activity. This high respiration activity allowed E. coli to produce more biomass and more reactive oxygen species that were controlled by the higher activity of the antioxidant defenses (SOD, peroxidase, and catalase) and the iron-sulfur cluster repair systems.
2022-06-30 | GSE203540 | GEO
Project description:Bacterial lipopolysaccharide-induced inflammation promotes iron accumulation in human adipocytes
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Project description:Iron accumulation drives fibrosis, senescence, and the senescence-associated secretory phenotype
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Project description:Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload evoked by FBXL5 ablation gives rise to oxidative stress, tissue damage, inflammation and compensatory proliferation in hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting effect of FBXL5 deficiency in the liver is also operative in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis induced by iron overload. Dysregulation of FBXL5-mediated cellular iron homeostasis was also found to be associated with poor prognosis in human HCC, implicating FBXL5 plays a significant role in defense against hepatocarcinogenesis.
2019-03-09 | GSE124370 | GEO
Project description:Nutrient autophagy factor 1 (NAF-1) is an iron-sulfur protein found on the outer mitochondrial membrane and the ER. Recent studies highlighted an important role for NAF-1 in regulating autophagy via interaction with BCL-2. We recently reported that the level of NAF-1 is elevated in cancer cells and that NAF-1 is required for tumor growth. Here we report that shRNA suppression of NAF-1 results in the activation of apoptosis in xenograft tumors and cancer cells grown in culture. Suppression of NAF-1 resulted in a depletion in the cytosolic iron pool, facilitated uptake of iron, and accumulation of iron and ROS in mitochondria, a shift to glycolysis and glutaminolysis, and the activation of cellular stress pathways associated with HIF1α, AMPK and mTOR. Suppression of NAF-1 in breast cancer cells appears therefore to reduce their tumorigenicity by interfering with cellular iron distribution and energy metabolism resulting in the activation of apoptosis.
2016-02-05 | GSE66158 | GEO