Page 95 - Haematologica April 2020

Red Cell Biology & its Disorders
Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis
Sandro Altamura,1,2,* Naidu M. Vegi,3* Philipp S. Hoppe,4 Timm Schroeder,4 Michaela Aichler,5 Axel Walch,5 Katarzyna Okreglicka,6 Lothar Hültner,7 Manuela Schneider,8 Camilla Ladinig,7 Cornelia Kuklik-Roos,7
Josef Mysliwietz,9 Dirk Janik,5 Frauke Neff,5 Birgit Rathkolb,10-12
Martin Hrabé de Angelis,11-13 Christian Buske,3 Ana Rita da Silva,1,2 Katja Muedder,1,2 Marcus Conrad,14 Tomas Ganz,15 Manfred Kopf,6 Martina U. Muckenthaler1,2 and Georg W. Bornkamm7,#
*These authors contributed equally to this work
1Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany; 2Molecular Medicine Partnership Unit, Heidelberg, Germany; 3Institute of Experimental Cancer Research, Universitätsklinikum Ulm, Ulm, Germany; 4Department of Biosystems Bioscience and Engineering, ETH Zürich, Basel, Switzerland; 5Research Unit Analytical Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany; 6Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland; 7Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany; 8Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, München, Germany; 9Institute of Molecular Immunology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany; 10Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, Genzentum, München, Germany; 11Institute of Experimental Genetics, Geman Mouse Clinic (GMC), Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany; 12German Center for Diabetes Research (DZD), Neuherberg, Germany; 13Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany; 14Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany and 15Departments of Medicine and Pathology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
ABSTRACT
Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid per- oxides to the respective alcohols thereby stabilizing oxidation prod- ucts of unsaturated fatty acids. During reticulocyte maturation, lipid peroxi- dation mediated by 15-lipoxygenase in humans and rabbits and by 12/15- lipoxygenase (ALOX15) in mice was considered the initiating event for the elimination of mitochondria but is now known to occur through mitophagy. Yet, genetic ablation of the Alox15 gene in mice failed to provide evidence for this hypothesis. We designed a different genetic approach to tackle this open conundrum. Since either other lipoxygenases or non-enzymatic autooxida- tive mechanisms may compensate for the loss of Alox15, we asked whether ablation of Gpx4 in the hematopoietic system would result in the perturba- tion of reticulocyte maturation. Quantitative assessment of erythropoiesis indices in the blood, bone marrow (BM) and spleen of chimeric mice with Gpx4 ablated in hematopoietic cells revealed anemia with an increase in the fraction of erythroid precursor cells and reticulocytes. Additional dietary vita- min E depletion strongly aggravated the anemic phenotype. Despite strong extramedullary erythropoiesis reticulocytes failed to mature and accumulated large autophagosomes with engulfed mitochondria. Gpx4-deficiency in hematopoietic cells led to systemic hepatic iron overload and simultaneous severe iron demand in the erythroid system. Despite extremely high erythro- poietin and erythroferrone levels in the plasma, hepcidin expression remained unchanged. Conclusively, perturbed reticulocyte maturation in response to Gpx4 loss in hematopoietic cells thus causes ineffective erythro- poiesis, a phenotype partially masked by dietary vitamin E supplementation.
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):937-950
Correspondence:
GEORG W. BORNKAMM
georg.bornkamm@t-online.de
Received: November 24, 2018. Accepted: June 20, 2019. Pre-published: June 27, 2019.
doi:10.3324/haematol.2018.212977
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/937
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