Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IRP1 deficiency alters mitochondrial metabolism

ABSTRACT: Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2 (HIF2) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Albert Koulman

PROVIDER: MSV000100449 | MassIVE | Tue Jan 13 05:13:00 GMT 2026

REPOSITORIES: MassIVE

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IRP1 deficiency triggers metabolic reprograming, increases insulin sensitivity and protects mice against metabolic syndrome pathologies

Project description:Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. Irp1-/- mice are viable but develop polycythemia. We report that these animals also exhibit fasting hypoglycemia and are protected against high fat diet-induced hyperglycemia and liver steatosis. Mechanistically, proteomics analysis revealed mitochondrial dysfunction in Irp1-/-livers. Seahorse assays validated impaired respiratory capacity in primary hepatocytes but also differentiated myotubes from Irp1-/- mice, which caused a switch from oxidative phosphorylation to glycolytic metabolism for energy production. This was accompanied by increased insulin sensitivity and glucose uptake by skeletal muscles. However, under conditions of metabolic stress or iron restriction, IRP1 deficiency prevented appropriate mitochondrial iron supply. Mitochondrial dysfunction and inefficient energy production caused metabolic rewiring and accumulation of metabolites in skeletal muscles of Irp1-/- mice, making them unavailable for gluconeogenesis in the liver. Thus, IRP1 emerges as an important metabolic regulator.

2025-12-17 | PXD051897 | Pride

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [II]

Project description:Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

2021-05-24 | GSE161646 | GEO

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [I]

2021-05-24 | GSE161644 | GEO

Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction.

Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR. Control (FLOX) and PGC-1a skeletal muscle specific knock out (MKO) mice were placed on a control diet [C] or a calorie restriction diet [CR] for 12 weeks. RNA was isolated from TA/EDL muscles for microarray analysis. The following numbers of mice were analyzed from each group: C FLOX: n = 6; C MKO: n = 7; CR FLOX: n = 6; CR MKO: n = 7. Mice were mixed C57/BL6 and 129 background.

2012-02-04 | E-GEOD-34773 | biostudies-arrayexpress

Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction.

2012-02-04 | GSE34773 | GEO

Expression data from 2-amino acetophenone (2-AA) treated mouse Skeletal muscle

Project description:Metabolic responses begin promptly upon the initiation of infection, and progress as a series of coordinated events. Mitochondria may play a key role in the development of insulin resistance. Reduced energy production and mitochondrial dysfunctional may further favor infection, and be an important step in the establishment of chronic and persistent infections. We have used mouse skeletal muscle transcriptome data which have led to the hypothesis that 2-AA causes harm to the host by triggering mitochondrial dysfunction in skeletal muscle. The gastrocnemius muscles were isolated from control and 4days 2-AA treated mouse for RNA extraction and hybridization on Affymetrix microarrays.

2013-01-28 | E-GEOD-43779 | biostudies-arrayexpress

Expression data from 2-amino acetophenone (2-AA) treated mouse Skeletal muscle

2013-01-28 | GSE43779 | GEO

Gene expression from Prep1-ablated mice

Project description:The homeodomain transcription factor Prep1 was previously shown to regulate insulin sensitivity. Our aim was to study the specific role of Prep1 for the regulation of energy metabolism in skeletal muscle. Muscle specific ablation of Prep1 resulted in increased expression of respiratory chain subunits. This finding was consistent with an increase in mitochondrial enzyme activity without affecting mitochondrial volume fraction as assessed by electron microscopy. Metabolic phenotyping revealed no differences in daily energy expenditure or body composition. However, during treadmill exercise challenge, Prep1 ablation resulted in a higher maximal oxidative capacity and better endurance. Elevated PGC-1Î± expression was identified as a cause for increased mitochondrial capacity in Prep1-ablated mice. Prep1 stabilizes p160 Mybbp1a, a known inhibitor of PGC-1Î± activity. Thereby, P160 protein levels were significantly lower in muscle of Prep1-ablated mice. By a ChIPseq approach, PREP1-binding sites in genes encoding mitochondrial components (e.g. Ndufs2) were identified that might be responsible for elevated OXPHOS proteins in the muscle of Prep1 nullmutants. These results suggest that Prep1 exhibits additional direct effects on regulation of mitochondrial proteins. We therefore conclude that Prep1 is a regulator of oxidative phosphorylation components via direct and indirect mechanisms. Consequence of Prep1 ablation in skeletal muscle was investigated in Prep1deltaSM mice and compared to Prep1 flox mice, both on C57BL/6 background. 4 mice of each genotype were used to extract RNA from the tibialis anterior muscle.

2014-01-01 | E-GEOD-52424 | biostudies-arrayexpress

Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle (compound 197 experiments)

Project description:There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored in an in vitro L6 model. This model demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle model to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.

2017-07-26 | GSE101845 | GEO

Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle (compound 177 experiments)

2017-07-26 | GSE101844 | GEO