Mitochondria in the Regulation of Terminal Erythropoiesis

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PROJECT SUMMARY/ABSTRACT The massive daily production of 200 billion red blood cells (RBCs) requires a remarkable coordination of erythroid cell differentiation and maturation, with processes that are implicated in erythroid enucleation. Alterations in regulatory mechanisms that control the terminal erythroid cell maturation and enucleation are implicated in erythroid and other disorders. Limited knowledge of these processes have been an impediment to therapy interventions and large-scale RBC production. Our long-standing focus on the transcription factor Foxo3 that is a central regulator of terminal erythropoiesis led us to identifying mitochondria as critical and dynamic regulators in these processes. We recently showed that mitochondria are actively regulating erythroid cell enucleation. Notably, we found exogenous pyruvate – a product of glycolysis – but not in situ produced pyruvate via glycolysis fuel mitochondria and sustains erythroid enucleation suggesting an unanticipated and significant function for exogenous pyruvate in this process. Our ongoing studies extend these findings and suggest that ATP-independent mitochondrial functions as well as mitochondrial-related pathways including clearance may be central to terminal erythropoiesis and their alterations implicated in disease. Our combined studies raise the possibility that mitochondria might integrate and coordinate several functions necessary for erythroid cell maturation prior and during enucleation. To further address mitochondrial functions in terminal erythropoiesis, we will accomplish the following: (Aim 1) we will investigate the contribution of mitochondrial clearance to erythroid cell maturation vs. enucleation; (Aim 2) we will investigate the contribution of mitochondrial network and morphology to the regulation of erythroid cell maturation vs. enucleation, and (Aim 3) we will address the specific pyruvate-mediated pathway that fuel mitochondria during terminal erythropoiesis. These studies are likely to expose a new mechanism of erythroid cell maturation and enucleation and to generate critical information for developing new means towards novel therapies and improving RBC production.