RNASeq from "a cell-nonautonomous heme acquisition pathway enables erythroid hemoglobinization under stress"

Heme is an essential iron-containing cofactor synthesized in mitochondria through a conserved eight-step enzymatic pathway. Cells have been thought to manage their own heme supply independently. However, over 1,000 proteins contribute to the production, transport, and regulation of the cofactor. During terminal erythroid differentiation, cells lose their mitochondria yet continue to make hemoglobin, implying a non-canonical, cell-nonautonomous heme source. We show that under stress, erythroid precursors import heme through the permease Heme Responsive Gene 1 (HRG1), which localizes to the plasma membrane and accumulates during stress erythropoiesis, an accelerated production of red blood cells outside the bone marrow in response to anemia. HRG1 loss impaired heme uptake, inhibited terminal erythroid differentiation, and caused anemia. With beta-thalassemia mice, partial loss of HRG1 improved ineffective erythropoiesis, underscoring the importance of balanced heme import. These findings reveal intercellular heme sharing and identify HRG1 as a potential therapeutic target in hemoglobinopathies.