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Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study

Familial hypobetalipoproteinemia is a metabolic disorder mainly caused by mutations in the apolipoprotein B gene. In its homozygous form it can lead without treatment to severe ophthalmological and neurological manifestations. In contrast, the heterozygous form is generally asymptomatic but associat...

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Autores principales: Cloos, Anne-Sophie, Daenen, Laura G. M., Maja, Mauriane, Stommen, Amaury, Vanderroost, Juliette, Van Der Smissen, Patrick, Rab, Minke, Westerink, Jan, Mignolet, Eric, Larondelle, Yvan, Terrasi, Romano, Muccioli, Giulio G., Dumitru, Andra C., Alsteens, David, van Wijk, Richard, Tyteca, Donatienne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940373/
https://www.ncbi.nlm.nih.gov/pubmed/33708142
http://dx.doi.org/10.3389/fphys.2021.638027
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author Cloos, Anne-Sophie
Daenen, Laura G. M.
Maja, Mauriane
Stommen, Amaury
Vanderroost, Juliette
Van Der Smissen, Patrick
Rab, Minke
Westerink, Jan
Mignolet, Eric
Larondelle, Yvan
Terrasi, Romano
Muccioli, Giulio G.
Dumitru, Andra C.
Alsteens, David
van Wijk, Richard
Tyteca, Donatienne
author_facet Cloos, Anne-Sophie
Daenen, Laura G. M.
Maja, Mauriane
Stommen, Amaury
Vanderroost, Juliette
Van Der Smissen, Patrick
Rab, Minke
Westerink, Jan
Mignolet, Eric
Larondelle, Yvan
Terrasi, Romano
Muccioli, Giulio G.
Dumitru, Andra C.
Alsteens, David
van Wijk, Richard
Tyteca, Donatienne
author_sort Cloos, Anne-Sophie
collection PubMed
description Familial hypobetalipoproteinemia is a metabolic disorder mainly caused by mutations in the apolipoprotein B gene. In its homozygous form it can lead without treatment to severe ophthalmological and neurological manifestations. In contrast, the heterozygous form is generally asymptomatic but associated with a low risk of cardiovascular disease. Acanthocytes or thorny red blood cells (RBCs) are described for both forms of the disease. However, those morphological changes are poorly characterized and their potential consequences for RBC functionality are not understood. Thus, in the present study, we asked whether, to what extent and how acanthocytes from a patient with heterozygous familial hypobetalipoproteinemia could exhibit altered RBC functionality. Acanthocytes represented 50% of the total RBC population and contained mitoTracker-positive surface patches, indicating the presence of mitochondrial fragments. While RBC osmotic fragility, calcium content and ATP homeostasis were preserved, a slight decrease of RBC deformability combined with an increase of intracellular free reactive oxygen species were observed. The spectrin cytoskeleton was altered, showing a lower density and an enrichment in patches. At the membrane level, no obvious modification of the RBC membrane fatty acids nor of the cholesterol content were detected but the ceramide species were all increased. Membrane stiffness and curvature were also increased whereas transversal asymmetry was preserved. In contrast, lateral asymmetry was highly impaired showing: (i) increased abundance and decreased functionality of sphingomyelin-enriched domains; (ii) cholesterol enrichment in spicules; and (iii) ceramide enrichment in patches. We propose that oxidative stress induces cytoskeletal alterations, leading to increased membrane stiffness and curvature and impaired lipid lateral distribution in domains and spicules. In addition, ceramide- and spectrin-enriched patches could result from a RBC maturation defect. Altogether, the data indicate that acanthocytes are associated with cytoskeletal and membrane lipid lateral asymmetry alterations, while deformability is only mildly impaired. In addition, familial hypobetalipoproteinemia might also affect RBC precursors leading to disturbed RBC maturation. This study paves the way for the potential use of membrane biophysics and lipid vital imaging as new methods for diagnosis of RBC disorders.
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spelling pubmed-79403732021-03-10 Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study Cloos, Anne-Sophie Daenen, Laura G. M. Maja, Mauriane Stommen, Amaury Vanderroost, Juliette Van Der Smissen, Patrick Rab, Minke Westerink, Jan Mignolet, Eric Larondelle, Yvan Terrasi, Romano Muccioli, Giulio G. Dumitru, Andra C. Alsteens, David van Wijk, Richard Tyteca, Donatienne Front Physiol Physiology Familial hypobetalipoproteinemia is a metabolic disorder mainly caused by mutations in the apolipoprotein B gene. In its homozygous form it can lead without treatment to severe ophthalmological and neurological manifestations. In contrast, the heterozygous form is generally asymptomatic but associated with a low risk of cardiovascular disease. Acanthocytes or thorny red blood cells (RBCs) are described for both forms of the disease. However, those morphological changes are poorly characterized and their potential consequences for RBC functionality are not understood. Thus, in the present study, we asked whether, to what extent and how acanthocytes from a patient with heterozygous familial hypobetalipoproteinemia could exhibit altered RBC functionality. Acanthocytes represented 50% of the total RBC population and contained mitoTracker-positive surface patches, indicating the presence of mitochondrial fragments. While RBC osmotic fragility, calcium content and ATP homeostasis were preserved, a slight decrease of RBC deformability combined with an increase of intracellular free reactive oxygen species were observed. The spectrin cytoskeleton was altered, showing a lower density and an enrichment in patches. At the membrane level, no obvious modification of the RBC membrane fatty acids nor of the cholesterol content were detected but the ceramide species were all increased. Membrane stiffness and curvature were also increased whereas transversal asymmetry was preserved. In contrast, lateral asymmetry was highly impaired showing: (i) increased abundance and decreased functionality of sphingomyelin-enriched domains; (ii) cholesterol enrichment in spicules; and (iii) ceramide enrichment in patches. We propose that oxidative stress induces cytoskeletal alterations, leading to increased membrane stiffness and curvature and impaired lipid lateral distribution in domains and spicules. In addition, ceramide- and spectrin-enriched patches could result from a RBC maturation defect. Altogether, the data indicate that acanthocytes are associated with cytoskeletal and membrane lipid lateral asymmetry alterations, while deformability is only mildly impaired. In addition, familial hypobetalipoproteinemia might also affect RBC precursors leading to disturbed RBC maturation. This study paves the way for the potential use of membrane biophysics and lipid vital imaging as new methods for diagnosis of RBC disorders. Frontiers Media S.A. 2021-02-23 /pmc/articles/PMC7940373/ /pubmed/33708142 http://dx.doi.org/10.3389/fphys.2021.638027 Text en Copyright © 2021 Cloos, Daenen, Maja, Stommen, Vanderroost, Van Der Smissen, Rab, Westerink, Mignolet, Larondelle, Terrasi, Muccioli, Dumitru, Alsteens, van Wijk and Tyteca. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Cloos, Anne-Sophie
Daenen, Laura G. M.
Maja, Mauriane
Stommen, Amaury
Vanderroost, Juliette
Van Der Smissen, Patrick
Rab, Minke
Westerink, Jan
Mignolet, Eric
Larondelle, Yvan
Terrasi, Romano
Muccioli, Giulio G.
Dumitru, Andra C.
Alsteens, David
van Wijk, Richard
Tyteca, Donatienne
Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study
title Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study
title_full Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study
title_fullStr Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study
title_full_unstemmed Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study
title_short Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia – A Case Study
title_sort impaired cytoskeletal and membrane biophysical properties of acanthocytes in hypobetalipoproteinemia – a case study
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940373/
https://www.ncbi.nlm.nih.gov/pubmed/33708142
http://dx.doi.org/10.3389/fphys.2021.638027
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