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Iron deficiency induces maturation-dependent loss of pancreatic β-cells.

ABSTRACT: Pancreatic β-cells maintain glucose homeostasis by secreting insulin in response to rising blood glucose, a process fueled by mitochondrial ATP production. Iron, a core cofactor in the electron transport chain, is essential for this metabolic coupling. While the cytotoxic effects of iron overload are well known, the role of iron sufficiency during β-cell development remains unclear. Here, we identify a maturation-dependent requirement for iron in mouse and human β-cells. Using chemical chelation and genetic disruption of transferrin receptor (TFRC)-mediated uptake, we show that immature β-cells depend on iron during metabolic transition to functional maturity. Iron restriction at this stage impairs oxidative metabolism and compromises survival. In contrast, mature β-cells remain resilient to iron depletion, revealing a developmental switch in iron dependency. These findings establish iron as a key metabolic cue in β-cell development and suggest strategies to generate fully functional stem cell-derived β-cells for diabetes modeling and cell replacement therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296443 | GEO | 2025/12/22

REPOSITORIES: GEO

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Iron deficiency induces maturation-dependent loss of pancreatic β-cells.

Project description:Pancreatic β-cells maintain glucose homeostasis by secreting insulin in response to rising blood glucose, a process fueled by mitochondrial ATP production. Iron, a core cofactor in the electron transport chain, is essential for this metabolic coupling. While the cytotoxic effects of iron overload are well known, the role of iron sufficiency during β-cell development remains unclear. Here, we identify a maturation-dependent requirement for iron in mouse and human β-cells. Using chemical chelation and genetic disruption of transferrin receptor (TFRC)-mediated uptake, we show that immature β-cells depend on iron during metabolic transition to functional maturity. Iron restriction at this stage impairs oxidative metabolism and compromises survival. In contrast, mature β-cells remain resilient to iron depletion, revealing a developmental switch in iron dependency. These findings establish iron as a key metabolic cue in β-cell development and suggest strategies to generate fully functional stem cell-derived β-cells for diabetes modeling and cell replacement therapy.

2025-12-23 | GSE296435 | GEO

Effect of R22W mutation in TFRC gene on gene expression in PBMCs

Project description:TFRC, also known as CD71, regulates the uptake of transferrin-bound iron into cells through receptor-mediated endocytosis. In a patient with a combined immunodeficiency, we identified a homozygous missense mutation in TFRC gene leading to R22W amino acid change in the cytoplasmic tail of the receptor. This mutation impairs the endocytosis of TFRC, which results in profound aberrations in the immune system.

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Impact of Tfrc deficiency on gut microbiome [16s rRNA-seq]

Project description:Iron metabolism is pivotal for cell fitness in the mammalian host. However, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71-mediated iron metabolism cell-intrinsically controls ILC3 maintenance, cytokine production and host protection against Citrobacter rodentium infection, and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc deficiency reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a ligand-dependent transcription factor and a key ILC3 regulator. Furthermore, consistent with its role in generation of Ahr ligand, microbiome exerts a negative impact on CD71 expression in an Ahr-dependent manner. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting an active suppression of CD71 by Ahr. Iron overload partially restores defective ILC3 compartment in the small intestine of Ahr-deficient mice, representing compensatory action of CD71 upregulation during Ahr deficiency. Mechanistically, Ahr directly binds to the promoter region of the Tfrc locus to inhibit Tfrc transcription. These data collectively demonstrate an under-appreciated role of the Ahr-CD71-iron axis in regulation of ILC3 maintenance and function.

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Proteomic analyses of iron deprived NK92 cells with deferoxamine or PPMX-T003

Project description:This work aims to detect the differentially expressed proteins between transferrin receptor 1 inhibition and iron chelation in a natural killer cell lymphoma-derived cell line NK92. Cells were treated with 500 μM deferoxamine or 10 μg/mL PPMX-T003 (an anti-transferrin receptor 1 inhibitory antibody) for 24 hours and lysed with RIPA buffer supplied with a proteasome inhibitor cocktail and a phosphatase inhibitor.

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Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function

Project description:Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron – a critical nutritional trace element – on ILC2 function and asthma pathogenesis. In the lungs, transferrin receptor 1 (TfR1) is rapidly upregulated and functional during ILC2 activation, while blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprograms ILC2 metabolism, inducing a HIF-1a-driven upregulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, in vivo iron chelation or induction of hypoferremia notably reduces the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induce TfR1 during activation, while iron deprivation reduces effector functions. Finally, we found a negative relation between circulating ILC2 TfR1 expression and airway function in cohorts of patients with asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function.

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Project description:The transferrin receptor 1 (TfR1), encoded by TFRC gene, is the gatekeeper of cellular iron uptake for cells. A variety of molecular mechanisms are at work to tightly regulate TfR1 expression, and abnormal TfR1 expression was associated with diseases. In the current study, to figure out the regulation pattern of TfR1, we cloned and overexpressed human TFRC gene in HeLa cells. RNA-sequencing (RNA-seq) was used to analyze the global transcript level on overexpression-treated (OE) and normal control (NC) cell samples. 1669 differentially expressed genes (DEGs) were identified between OE and NC, and Gene ontology (GO) analysis for DEGs were carried out. It was found that lots of DEGs were associated with ion transmembrane transport and immunity. Moreover, the network was constructed on basis of DEGs regulating ion transport and immunity, the results revealed that TFRC was the node gene of the network, further suggesting that precisely controlled TfR1 expression might be not only essential for iron homeostasis, but also globally important for cell physiology, including ion transport and immunity.

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