Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis.

Autor:	Altamura S; Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, Heidelberg, Germany., Vegi NM; Institute of Experimental Cancer Research, Universitätsklinikum Ulm, Ulm, Germany., Hoppe PS; Department of Biosystems Bioscience and Engineering, ETH Zürich, Basel, Switzerland., Schroeder T; Department of Biosystems Bioscience and Engineering, ETH Zürich, Basel, Switzerland., Aichler M; Research Unit Analytical Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany., Walch A; Research Unit Analytical Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany., Okreglicka K; Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland., Hültner L; Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany., Schneider M; Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, München, Germany., Ladinig C; Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany., Kuklik-Roos C; Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany., Mysliwietz J; Institute of Molecular Immunology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany., Janik D; Research Unit Analytical Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany., Neff F; Research Unit Analytical Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany., Rathkolb B; Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, Genzentum, München, Germany.; Institute of Experimental Genetics, Geman Mouse Clinic (GMC), Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany., de Angelis MTH; Institute of Experimental Genetics, Geman Mouse Clinic (GMC), Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.; German Center for Diabetes Research (DZD), Neuherberg, Germany.; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany., Buske C; Institute of Experimental Cancer Research, Universitätsklinikum Ulm, Ulm, Germany., Silva ARD; Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, Heidelberg, Germany., Muedder K; Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, Heidelberg, Germany., Conrad M; Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany., Ganz T; Departments of Medicine and Pathology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Kopf M; Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland., Muckenthaler MU; Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, Heidelberg, Germany., Bornkamm GW; Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany georg.bornkamm@t-online.de.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2020 Apr; Vol. 105 (4), pp. 937-950. Date of Electronic Publication: 2019 Jun 27.
DOI:	10.3324/haematol.2018.212977
Abstrakt:	Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation 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 autooxidative mechanisms may compensate for the loss of Alox15 , we asked whether ablation of Gpx4 in the hematopoietic system would result in the perturbation 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 vitamin 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 erythropoietin 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 erythropoiesis, a phenotype partially masked by dietary vitamin E supplementation. (Copyright© 2020 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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