ALPHA 2-MACROGLOBULIN, A NATURAL LRP1 LIGAND, STIMULATES MITOPHAGY IN ERYTHROLEUKEMIC CELLS

JACOB J; RETA P; CASTRO PÉREZ S; VIEYRA C; FADER CM

Mendoza

Congreso; LVIII ANNUAL MEETING OF SAIB; 2022

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

Erythropoiesis is a highly regulated process by which red blood cells are generated from hematopoietic stem and progenitor cells (HSPCs) located in the bone marrow. During this process, the erythroid precursors undergo a series of physiological changes necessary for the maturation of the erythrocyte. These changes involve membranes remodeling, cell volume decrease, specific protein synthesis such as hemoglobin, membranous organelles clearance by autophagy and enucleation. Autophagy is a degradation and recycling process by which cytosolic macromolecules and even entire organelles are transported to lysosomes. During mitophagy (a specialized autophagic mechanism), mitochondria become trapped in double-membrane vesicles (autophagosomes) and are subsequently degraded and removed by autophagosome-lysosome fusion. This process is related with red blood cells differentiation and maturation, as well as certain mechanisms involved in chemotherapy treatment resistance of particular types of leukemia. On the other hand, low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane endocytic receptor involved in many cellular processes, such as cell migration, apoptosis, autophagy and the metabolism of molecules such as alpha-2-macroglobulin (α2m). Previously, we have shown that hemin, a physiological inducer of erythropoiesis, is capable of inducing autophagy in the erythroid cell line K562 through its binding to LRP1. We want to determine the specific role of the LRP1 receptor, as a mitophagy modulator, during human terminal erythropoiesis using different ligands (hemin, LDL and α2m). Interestingly, our recent results indicate that α2m, which is a natural ligand of LRP1 and is not an inducer of erythropoiesis (like hemin), is also capable of autophagy stimulation in erythroleukemic cells. Furthermore, as we have identified the presence of mitochondria inside autophagosomes of α2m incubated K562 cells, we propose that α2m is responsible for the mitophagy induction. These findings lead us to consider that LRP1 would be a key receptor in the erythropoietic process, participating in mitophagy stimulation during the erythroid maturation process. This study could provide valuable knowledge for understanding the physiology of the erythroid maturation process, as well as for possible treatment developments against some pathologies associated with this process, such as leukemia.