Abstract
The reduced iron usage induced by the suppression of erythropoiesis is a major cause of the systemic iron overload in CBS knockout (CBS−/−) mice. However, the relevant mechanisms are unknown. Here, we examined changes in granulocyte/erythroid cell ratios, iron content, and expression of iron-metabolism proteins, including; two key enzymes involved in the heme biosynthetic pathway, ALAS2 (delta-aminolevulinate synthase 2) and FECH (ferrochelatase), a heme exporter from the cytosol and mitochondria, FLVCR (feline leukemia virus subgroup C cellular receptor) as well as EPO (erythropoietin), EPOR (erythropoietin receptor) and HIF-2α (hypoxia inducible factor-2 subunit α), in the blood, bone marrow or liver of CBS−/− (homozygous), CBS+/− (heterozygous) and CBS+/+ (Wild Type) mice. Our findings demonstrate that CBS deficiency can induce a significant reduction in the expression of ALAS2, FECH, FLVCR, HIF-2α, EPO, and EPOR as well as an increase in interleukin-6 (IL-6), hepcidin and iron content in the blood, bone marrow or liver of mice. We conclude that the suppression of erythropoiesis is mainly due to the CBS deficiency-induced disruption in the expression of heme biosynthetic enzymes and heme-transporter.
Highlights
The reduced iron usage induced by the suppression of erythropoiesis is a major cause of the systemic iron overload in CBS knockout (CBS−/−) mice
We first examined in detail the effects of CBS−/− on red blood cell (RBC), hematocrit (HCT), hemoglobin (Hb), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), iron, interleukin-6 (IL-6), and hepcidin contents in the blood, and the ratio of granulocyte/erythroid cells, iron, ferritin-light chain (Ft-L) and ferritin-heavy chain (Ft-H) levels, as well as deltaaminolevulinate synthase 2 (ALAS2) and ferrochelatase (FECH), two key enzymes involved in the heme biosynthetic pathway, and feline leukemia virus subgroup C
We investigated the expression of iron transport proteins, including transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1), iron storage proteins Ft-L and Ft-H, iron regulatory hormone and proteins (IRPs), and other relevant molecules, including erythropoietin (EPO) and its receptor (EPOR), hypoxia inducible factor-2 subunit α (HIF-2α), phosphorylated Janus kinase 2 (p-JAK2) and erythroferrone (ERFE) in the bone marrow, bone marrowderived macrophages (BMDMs) or liver of CBS−/−, CBS+/−, and CBS+/+ mice
Summary
The reduced iron usage induced by the suppression of erythropoiesis is a major cause of the systemic iron overload in CBS knockout (CBS−/−) mice. We examined changes in granulocyte/erythroid cell ratios, iron content, and expression of iron-metabolism proteins, including; two key enzymes involved in the heme biosynthetic pathway, ALAS2 (delta-aminolevulinate synthase 2) and FECH (ferrochelatase), a heme exporter from the cytosol and mitochondria, FLVCR (feline leukemia virus subgroup C cellular receptor) as well as EPO (erythropoietin), EPOR (erythropoietin receptor) and HIF-2α (hypoxia inducible factor-2 subunit α), in the blood, bone marrow or liver of CBS−/− (homozygous), CBS+/− (heterozygous) and CBS+/+ (Wild Type) mice. Our findings demonstrated that CBS deficiency could induce a significant reduction in the expression of ALAS2, FECH, and FLVCR, alongside a significant increase in iron content in the bone marrow, indicating that the suppression of erythropoiesis is mainly due to the inhibitory effects of CBS deficiency on two key enzymes involved in the heme biosynthetic pathway, and on the transport of heme from the cytosol and mitochondria. The reduced expression of EPO in CBS−/− mice could lead to an increase in CFU-E (colony-forming unit erythroids) apoptosis and reduce the number of erythroblasts, which may be one of the molecular mechanisms involved in the suppression of erythropoiesis in CBS−/− mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
