1. Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis
- Author
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Juliette Vanderroost, Donatienne Tyteca, Catherine Léonard, Amaury Stommen, Christiane Vermylen, Miikka Vikkula, Adrien Paquot, Manuel Guthmann, Didier Vertommen, Louise Conrard, Hélène Pollet, Mélanie Carquin, Maxime Lingurski, Giulio G. Muccioli, Laurent Gatto, Theodore Killian, Mark H. Rider, Patrick Van Der Smissen, Marine Ghodsi, Sébastien Pyr dit Ruys, Pascal Brouillard, Anne-Sophie Cloos, and UCL - SSS/DDUV - Institut de Duve
- Subjects
0301 basic medicine ,Erythrocytes ,lysophosphatidylserine ,Membrane Fluidity ,Hereditary elliptocytosis ,lcsh:QR1-502 ,amitriptyline ,spectrin cytoskeleton ,Ca2+ ,lipid domains ,membrane asymmetry ,membrane rigidity ,membrane curvature ,oxidative stress ,Biochemistry ,Article ,lcsh:Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Elliptocytosis ,0302 clinical medicine ,Membrane Microdomains ,hemic and lymphatic diseases ,medicine ,Humans ,Spectrin ,Molecular Biology ,Erythrocyte Membrane ,Elliptocytosis, Hereditary ,Phosphatidylserine ,medicine.disease ,Cell biology ,Red blood cell ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Cholesterol ,chemistry ,Lysophosphatidylserine ,Membrane curvature ,030220 oncology & carcinogenesis ,Acid sphingomyelinase ,Lysophospholipids ,medicine.drug - Abstract
[Authors equally contributed to the work : Hélène Pollet, Anne-Sophie Cloos] Red blood cell (RBC) deformability is altered in inherited RBC disorders but the mechanism behind this is poorly understood. Here, we explored the molecular, biophysical, morphological, and functional consequences of α-spectrin mutations in a patient with hereditary elliptocytosis (pEl) almost exclusively expressing the Pro260 variant of SPTA1 and her mother (pElm), heterozygous for this mutation. At the molecular level, the pEI RBC proteome was globally preserved but spectrin density at cell edges was increased. Decreased phosphatidylserine vs. increased lysophosphatidylserine species, and enhanced lipid peroxidation, methemoglobin, and plasma acid sphingomyelinase (aSMase) activity were observed. At the biophysical level, although membrane transversal asymmetry was preserved, curvature at RBC edges and rigidity were increased. Lipid domains were altered for membrane:cytoskeleton anchorage, cholesterol content and response to Ca2+ exchange stimulation. At the morphological and functional levels, pEl RBCs exhibited reduced size and circularity, increased fragility and impaired membrane Ca2+ exchanges. The contribution of increased membrane curvature to the pEl phenotype was shown by mechanistic experiments in healthy RBCs upon lysophosphatidylserine membrane insertion. The role of lipid domain defects was proved by cholesterol depletion and aSMase inhibition in pEl. The data indicate that aberrant membrane content and biophysical properties alter pEl RBC morphology and functionality.
- Published
- 2020
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