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Gu, W.* ; Wilkinson, N.* ; Fillebeen, C.* ; Blackburn, D.* ; Sahinyan, K.* ; Bonneil, E.* ; Zhao, T.* ; Luo, Z.* ; Soleimani, V.* ; Richard, V.* ; Borchers, C.H.* ; Koulman, A.* ; Jenkins, B.* ; Michalke, B. ; Zischka, H. ; Sailer, J. ; Venkataramani, V.* ; Iliopoulos, O.* ; Sweeney, G.* ; Pantopoulos, K.*

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies.

JCI insight 11:e183247 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 2α (HIF2α) 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Diabetes ; Glucose Metabolism ; Hepatology ; Metabolism ; Proteomics; Iron Regulatory Protein-1; Insulin Sensitivity; Hepatic Glucose; Mice; Erythropoiesis; Polycythemia; Hif2-alpha; Oxidation; Deletion; Hypoxia
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Zeitschrift JCI insight
Quellenangaben Band: 11, Heft: 4, Seiten: , Artikelnummer: e183247 Supplement: ,
Verlag Clarivate
Verlagsort Ann Arbor, Michigan
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit BioGeoChemistry and Analytics (BGC)
Institute of Molecular Toxicology and Pharmacology (TOX)
Förderungen Deutsche Forschungsgemeinschaft
Canadian Institutes of Health Research