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

作者：Sandro Altamura, Vegi M. Naidu, Philipp S. Hoppe, Timm Schroeder, Michaela Aichler, Axel Walch, Katarzyna Okreglicka, Lothar Hültner, Manuela Schneider, Camilla Ladinig, Cornelia Kuklik‐Roos, Josef Mysliwietz, Dirk Janik, Frauke Neff, Birgit Rathkolb, Martin Hrabě de Angelis, Christian Buske, Ana Rita da Silva, Katja Muedder, Marcus Conrad, Tomas Ganz, Manfred Köpf, Martina U. Muckenthaler, Georg W. Bornkamm · 发表于：Haematologica · 年份：2019 · DOI：10.3324/haematol.2018.212977 · 被引用次数：89 · 研究领域：Erythrocyte Function and Pathophysiology、Hemoglobinopathies and Related Disorders、Trace Elements in Health

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...