Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation
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ABSTRACT:
PROVIDER: PRJNA593727 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10590683.fastq.gz | Fastqsanger.gz | |||
| SRR10590684.fastq.gz | Fastqsanger.gz | |||
| SRR10590685.fastq.gz | Fastqsanger.gz | |||
| SRR10590686.fastq.gz | Fastqsanger.gz | |||
| SRR10590687.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: In previous work, we found that iron supplementation to cells rescues impairment of cell viability and proliferation upon lysosomal dysfunction due to inhibition of the vATPase complex. The goal of this study is to characterize the transcriptomic changes (RNA-seq) upon Bafilomycin mediated lysosomal dysfunction with and without iron (Ferric Ammonium Citrate) supplementation. Methods: mRNA profiles of wild type HEK293T cells treated +/- ferric ammonium citrate (0.1mg/ml) and +/- BafilomycinA1 (10nM) were generated by deep sequencing, in triplicate, using Illumina NextSeq500. Results: We mapped about 30-40 million sequence reads per sample to the human genome (build GRCh38). Conclusions: Our study characterizes the transcriptomic changes upon lysosomal dysfunction upon small molecule (Bafilomycin A1) inhibition of vATPase complex. We conclude that there are several notable trasncriptomic changes upon lysosomal dysfunction some of which are reversed by iron supplementation.
2019-12-06 | GSE141507 | GEO
Project description:The lysosome is an acidic multi-functional organelle with roles in macromolecular digestion, nutrient sensing, and signaling. However, why cells require acidic lysosomes to proliferate and which nutrients become limiting under lysosomal dysfunction are unclear. To address this, we performed CRISPR-Cas9-based genetic screens and identified cholesterol biosynthesis and iron uptake as essential metabolic pathways when lysosomal pH is altered. While cholesterol synthesis is only necessary, iron is both necessary and sufficient for cell proliferation under lysosomal dysfunction. Remarkably, iron supplementation restores cell proliferation under both pharmacologic and genetic-mediated lysosomal dysfunction. The rescue was independent of metabolic or signaling changes classically associated with increased lysosomal pH, uncoupling lysosomal function from cell proliferation. Finally, our experiments revealed that lysosomal dysfunction dramatically alters mitochondrial metabolism and hypoxia inducible factor (HIF) signaling due to iron depletion. Altogether, these findings identify iron homeostasis as the key function of lysosomal acidity for cell proliferation.
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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
Project description:Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload.
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Project description:Tumour-associated macrophages (TAMs), as one of the most abundant and phagocytic tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, which limits the function of antigen cross-presentation. How to selectively reprogram the antigen-destroying TAMs to a restorative phenotype for efficient anti-tumour immunity is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to M1-like phenotypes with tuned-down lysosomal function featured by attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus provoking adaptive immune response and sustained tumour regression. Our findings provide new insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.
2023-08-29 | PXD044911 | Pride
Project description:Lysosomal storage diseases (LSDs) comprised ~50 gene loci causing the accumulation of cellular material in the lysosome and associated defects in lysosomal function, but systematic molecular phenotyping is lacking. Here, we apply a nanoflow-based multi-omic single-shot technology (nMOST) workflow to simultaneously quantify HeLa cell proteomes and lipidomes from dozens of LSD mutants, revealing diverse molecular phenotypes. Defects in delivery of ferritin and its autophagic regulator NCOA4 to lysosomes (ferritinophagy) were pronounced in NPC2-/- cells, which correlated with increased lyso-phosphatidyl-choline species and dramatic multi-lamellar membrane structures visualized by cryo-electron tomography. Ferritinophagy defects correlated with loss of mitochondrial cristae, MICOS complex components, and electron transport chain complexes rich in iron-sulfur cluster proteins. Strikingly, these defects were rescued when iron was provided through the transferrin system. This resource reveals how loss of lysosomal function impacts organelle homeostasis in trans and highlights nMOST profiling as a discovery tool for illuminating distinct molecular phenotypes across LSDs.
2024-10-08 | PXD049336 | Pride
Project description:Regulatory T cells (Tregs) are known to maintain survival and suppressive function in the presence of high levels of extracellular lactic acid. However, the effect of lactic acid on Treg induction is not known. We therfore evaluated the effect of lactic acid on Treg induction and observed an increased induction of Tregs in the presence of lactic acid. This increase occurred in a glycolysis-independent, acidity-dependent manner.
2023-03-23 | GSE217536 | GEO
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:Aging affects iron homeostasis and erythropoiesis, as evidenced by tissue iron loading in rodents and common anemia in the elderly. Given thatred pulp macrophages (RPMs) continuously process iron, their cellular functions might be susceptible to age-dependent decline, affecting organismal iron metabolism and red blood cell (RBCs) parameters. However, little is known about the effects of aging on the functioning of RPMs. To study aging RPMs, we employed 10-11-months-old female mice that show serum iron deficiency and iron overload primarily in spleens compared to young controls. We observed that this is associated with iron loading, oxidative stress, diminished lysosomal activity, and decreased erythrophagocytosis rate in RPMs. We uncovered that these impairments of RPMs lead to the retention of senescent RBCs in the spleen, their excessive local hemolysis, and the formation of iron- and heme-rich large extracellular protein aggregates, likely derived from damaged ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, improves their ability to clear and degrade erythrocytes, and limits ferroptosis. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and the formation of iron-rich protein aggregates, and increases serum iron availability in aging mice. Using RPM-like cells, we show that diminished erythrophagocytic and lysosomal activities of RPMs can be attributed to a combination of increased iron levels and reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1). Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.
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Project description:To explore whether iron is required for BCR-induced H3K9 demethylation during B cell activation, we performed ChIP-seq to check the H3K9me2 modification in control (iron-normal) and iron-deficient B cells
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