Glycine is a key rate-limiting component of
heme biosynthesis in erythropoietic cells, where the high intracellular
glycine demand is primarily supplied by the
glycine transporter 1 (GlyT1). The impact of intracellular
glycine restriction after GlyT1 inhibition on hematopoiesis and
iron regulation is not well established. We investigated the effects of a potent and selective inhibitor of GlyT1,
bitopertin, on erythropoiesis and
iron homeostasis in rats. GlyT1 inhibition significantly affected erythroid
heme biosynthesis, manifesting as microcytic hypochromic regenerative
anemia with a 20% steady-state reduction in
hemoglobin. Reduced erythropoietic
iron utilization was characterized by down-regulation of the
transferrin receptor 1 (TfR1) on reticulocytes and modest increased
iron storage in the spleen. Hepatic
hepcidin expression was not affected. However, under the condition of reduced
heme biosynthesis with reduced
iron reutilization and increased storage
iron,
hepcidin at the lower and higher range of normal showed a striking role in tissue distribution of
iron. Rapid formation of
iron-positive inclusion bodies (IBs) was observed in circulating reticulocytes, with an ultrastructure of
iron-containing polymorphic mitochondrial remnants. IB or mitochondrial
iron accumulation was absent in bone marrow erythroblasts. In conclusion, GlyT1 inhibition in rats induced a steady-state microcytic hypochromic regenerative
anemia and a species-specific accumulation of uncommitted mitochondrial
iron in reticulocytes. Importantly, this
glycine-restricted
anemia provides no feedback signal for increased systemic
iron acquisition and the effects reported are pathogenetically distinct from systemic
iron-overload anemias and erythropoietic disorders such as acquired
sideroblastic anemia.