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Altamura, S.* ; Vegi, N.M.* ; Hoppe, P.S.* ; Schroeder, T.* ; Aichler, M. ; Walch, A.K. ; Okreglicka, K.* ; Hültner, L. ; Schneider, M.* ; Ladinig, C. ; Kuklik-Roos, C. ; Mysliwietz, J. ; Janik, D. ; Neff, F. ; Rathkolb, B. ; Hrabě de Angelis, M. ; Buske, C.* ; da Silva, A.R.* ; Muedder, K.* ; Conrad, M. ; Ganz, T.* ; Kopf, M.* ; Muckenthaler, M.U.* ; Bornkamm, G.W.

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

Haematologica 105, 937-950 (2020)
Publ. Version/Full Text Postprint DOI
Open Access Gold
Creative Commons Lizenzvertrag
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 ation of mitochondria but is now known to occur through mitophary Yet, ggenetic ablation of the Alox15 gene in mice failed to provice evidence or this hyppothesis. 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 extramedullaty 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hematopoiesis ; Iron Metabolism ; Red Cells; Beta-thalassemia Major; Oxidative Stress; Lipid-peroxidation; Dna-damage; Rabbit Reticulocytes; Cre Recombinase; E-deficiency; Lipoxygenase; 12/15-lipoxygenase; Gpx4
ISSN (print) / ISBN 0390-6078
e-ISSN 1592-8721
Quellenangaben Volume: 105, Issue: 4, Pages: 937-950 Article Number: , Supplement: ,
Publisher Ferrata Storti Foundation
Publishing Place Via Giuseppe Belli 4, 27100 Pavia, Italy
Reviewing status Peer reviewed