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Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice

Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (P...

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Autores principales: Das, Yannick, Swinkels, Daniëlle, Kocherlakota, Sai, Vinckier, Stefan, Vaz, Frédéric M., Wever, Eric, van Kampen, Antoine H. C., Jun, Bokkyoo, Do, Khanh V., Moons, Lieve, Bazan, Nicolas G., Van Veldhoven, Paul P., Baes, Myriam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884615/
https://www.ncbi.nlm.nih.gov/pubmed/33604342
http://dx.doi.org/10.3389/fcell.2021.632930
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author Das, Yannick
Swinkels, Daniëlle
Kocherlakota, Sai
Vinckier, Stefan
Vaz, Frédéric M.
Wever, Eric
van Kampen, Antoine H. C.
Jun, Bokkyoo
Do, Khanh V.
Moons, Lieve
Bazan, Nicolas G.
Van Veldhoven, Paul P.
Baes, Myriam
author_facet Das, Yannick
Swinkels, Daniëlle
Kocherlakota, Sai
Vinckier, Stefan
Vaz, Frédéric M.
Wever, Eric
van Kampen, Antoine H. C.
Jun, Bokkyoo
Do, Khanh V.
Moons, Lieve
Bazan, Nicolas G.
Van Veldhoven, Paul P.
Baes, Myriam
author_sort Das, Yannick
collection PubMed
description Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
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spelling pubmed-78846152021-02-17 Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice Das, Yannick Swinkels, Daniëlle Kocherlakota, Sai Vinckier, Stefan Vaz, Frédéric M. Wever, Eric van Kampen, Antoine H. C. Jun, Bokkyoo Do, Khanh V. Moons, Lieve Bazan, Nicolas G. Van Veldhoven, Paul P. Baes, Myriam Front Cell Dev Biol Cell and Developmental Biology Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis. Frontiers Media S.A. 2021-02-02 /pmc/articles/PMC7884615/ /pubmed/33604342 http://dx.doi.org/10.3389/fcell.2021.632930 Text en Copyright © 2021 Das, Swinkels, Kocherlakota, Vinckier, Vaz, Wever, van Kampen, Jun, Do, Moons, Bazan, Van Veldhoven and Baes. http://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 Cell and Developmental Biology
Das, Yannick
Swinkels, Daniëlle
Kocherlakota, Sai
Vinckier, Stefan
Vaz, Frédéric M.
Wever, Eric
van Kampen, Antoine H. C.
Jun, Bokkyoo
Do, Khanh V.
Moons, Lieve
Bazan, Nicolas G.
Van Veldhoven, Paul P.
Baes, Myriam
Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
title Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
title_full Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
title_fullStr Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
title_full_unstemmed Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
title_short Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
title_sort peroxisomal multifunctional protein 2 deficiency perturbs lipid homeostasis in the retina and causes visual dysfunction in mice
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884615/
https://www.ncbi.nlm.nih.gov/pubmed/33604342
http://dx.doi.org/10.3389/fcell.2021.632930
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