Defining the metabolic regulation of erythropoiesis

PROJECT SUMMARY The metabolic state of hematopoietic stem cells is an important contributor to self-renewal, however the metabolic changes controlling the differentiation of hematopoietic stem cells to erythrocytes is poorly understood. Here, I show preliminary data that that the malate-aspartate shuttle (MAS) impacts early erythropoiesis. The MAS is a well-studied mechanism in cells that transfers electrons in the form of NADH from the cytosol into the mitochondria, Specifically, disruption of the shuttle in vivo through conditional deletion of one its enzyme in an erythroid progenitor leads to significant anemia. Accordingly, I hypothesize that the MAS is required for redox homeostasis during early erythroid development and that failure of the MAS paves way for ineffective erythropoiesis. AIM I works to determine which erythroid differentiation stages requires the MAS. AIM II defines the molecular mechanism by which the MAS impacts erythropoiesis. For these, I am using both in vivo mouse models and in vitro CD34+ hematopoietic stem and progenitor cells. Together, these aims investigate whether reductive stress through the MAS during early erythropoiesis is an important contributor to ineffective erythropoiesis.