[Mechanistic insights into maintenance and disruption of membrane phosphatidylserine asymmetry in human erythrocytes: a survival strategy during their lifespan].

Abstract

Human erythrocytes retain phosphatidylserine (PS) only in the inner leaflet of plasma membranes during their 120-day lifespan to enforce membrane strengthen through associations with cytoskeletal proteins. Meanwhile, PS is exposed to the outer leaflet at the end of the lifespan for removal by phagocytosis of splenic macrophages. Consequently, their lifespan is determined by the localization of PS. PS-flippase activity of erythrocytes from an ATP11C-deficient patient was reduced by 90%, however, PS was unexposed in almost all erythrocytes from the patient. This suggests that flippase-independent mechanisms may retain PS in the inner leaflet. Depletion of cholesterol from erythrocyte membranes significantly facilitated PS exposure under low intracellular Ca²⁺ condition, indicating that cholesterol may block the lipid scrambling. In senescent erythrocytes, ATP11C level and the intracellular ATP and K⁺ concentrations were decreased in turn to reduce the flippase activity. The senescent erythrocytes easily exposed PS by raising a subtle amount of intracellular Ca²⁺ compared to young erythrocytes, indicating that the elevated intracellular Ca²⁺ concentration is a critical determinant of erythrocyte lifespan. We also assessed the erythrocytes from patients with renal anemia: the shortened lifespan of erythrocytes. We found that ATP11C expression level and the intracellular K⁺ concentration were decreased in the anemic erythrocytes, indicating that the early onset of aging is triggered by the PS exposure. Elucidating this mechanism would propose a novel treatment focused on extending erythrocyte's lifespan for renal anemia.