IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies
Iron regulatory protein 1 (IRP1) is a posttranscriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of 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 muscles, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.
Authors
- Christoph Börchers
- Bernhard Michalke (ORCID: https://orcid.org/0000-0001-6376-2588)
- Vahab D. Soleimani (ORCID: https://orcid.org/0000-0003-2154-4894)
- Wen Gu (ORCID: https://orcid.org/0000-0001-9765-7153)
- Benjamin Jenkins (ORCID: https://orcid.org/0000-0003-0038-9709)
- Nicole Wilkinson
- Vincent R. Richard (ORCID: https://orcid.org/0000-0001-7224-1290)
- Hans Zischka (ORCID: https://orcid.org/0000-0002-4047-1566)
- ALBERT KOULMAN
- Carine Fillebeen
- Éric Bonneil (ORCID: https://orcid.org/0000-0002-4039-3131)
- Darren M. Blackburn (ORCID: https://orcid.org/0000-0001-9084-7595)
- Korin Sahinyan (ORCID: https://orcid.org/0000-0002-2641-5250)
- Kostas Pantopoulos
- Judith Sailer (ORCID: https://orcid.org/0009-0001-2043-9673)
- Gary Sweeney
- Othon Iliopoulos
- Vivek Venkataramani
- Zhi Luo
- Tao Zhao
Institutions
- University of Ottawa (CA)
- York University (CA)
- Huazhong Agricultural University (CN)
- University of Cambridge (GB)
- Jewish General Hospital (CA)
- Helmholtz Zentrum München (DE)
- Massachusetts General Hospital (US)
- Institute for Research in Immunology and Cancer (CA)
- National Center for Tumor Diseases (DE)
- Wellcome/MRC Institute of Metabolic Science (GB)
- McGill University (CA)
- Technical University of Munich (DE)
- Université de Montréal (CA)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-01-06
- DOI
- https://doi.org/10.1172/jci.insight.183247
- Primary Topic
- Iron Metabolism and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Krebsforschungszentrum
- University of Alberta