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ResearchIn-Press PreviewHepatologyMetabolism Open Access | 10.1172/jci.insight.183247

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies

Wen Gu,1 Nicole Wilkinson,1 Carine Fillebeen,1 Darren Blackburn,1 Korin Sahinyan,1 Eric Bonneil,3 Tao Zhao,1 Zhi Luo,4 Vahab Soleimani,1 Vincent Richard,1 Christoph H. Borchers,1 Albert Koulman,5 Benjamin Jenkins,5 Bernhard Michalke,6 Hans Zischka,7 Judith Sailer,7 Vivek Venkataramani,8 Othon Iliopoulos,9 Gary Sweeney,10 and Kostas Pantopoulos1

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Gu, W. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Wilkinson, N. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Fillebeen, C. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Blackburn, D. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Sahinyan, K. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Bonneil, E. in: PubMed | Google Scholar |

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Zhao, T. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Luo, Z. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Soleimani, V. in: PubMed | Google Scholar |

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Richard, V. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Borchers, C. in: PubMed | Google Scholar |

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Koulman, A. in: PubMed | Google Scholar |

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Jenkins, B. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Michalke, B. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Zischka, H. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Sailer, J. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Venkataramani, V. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Iliopoulos, O. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Sweeney, G. in: PubMed | Google Scholar

1Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Canada

2Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, Canada

3Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada

4Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan, China

5Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom

6Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Research Unit Analytical BioGeoChemistry, Neuherberg, Germany

7Environmental Hygiene, Technical University Munich, Munich, Germany

8Department of Internal Medicine II and Department of Neurosurgery, University Hospital Würzburg; and Bavarian Cancer Research Center (BZKF), National Center for Tumor Diseases (NCT) WERA, Würzburg, Germany

9Department of Medicine, Hematology-Oncology Unit, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, United States of America

10Department of Biology, York University, Toronto, Canada

Find articles by Pantopoulos, K. in: PubMed | Google Scholar

Published January 6, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.183247.
Copyright © 2026, Gu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 6, 2026 - Version history
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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 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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