Unraveling the role of the putative ATPase ATP5MGL in beta-thalassemia

This project has been approved for funding - the activation procedure is still pending

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023

Hemoglobin, the oxygen carrier in mature red cells, is composed by two proteins: α-globin and β-globin. Mutations in the β-globin gene dysrupt hemoglobin formation causing β-thalassemia, a rare and invalidating hereditary disease present in countries of the Mediterranean area. In an unsuccessful attempt of forming more hemoglobin, the production of α-globin is enhanced. This causes the precipitation of toxic α-globin aggregates, that damage red cell precursors and impede their differentiation, causing anemia. A huge amount of energy, provided in the form of ATP, is required to properly support red cells differentiation and the degradation of excess α-globin. Several evidence suggest that thalassemic red cell precursors have a defective energy production and their differentiation can be improved enhancing ATP synthesis. So, understanding the machinery responsible for ATP production may improve our knowledge of the pathophysiology of β-thalassemia. A key player in this system is ATP synthase, an enzymatic complex composed of several subunits. The function of the subunit ATP5MGL is unknown, but its high and prevalent expression in red cells and information about the homologue ATP5MG function led us to hypothesize that ATP5MGL might have a crucial role in promoting red cells differentiation. Here, we will exploit in vitro and in vivo studies to investigate the role of ATP5MGL in physiologic and thalassemic red cells maturation and whether its inactivation hampers this process. The perspective of the study is to identify a novel potential therapeutic target for β-thalassemia, that, overriding the lack of energy, might help red cells differentiation.