TY - JOUR
T1 - Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice
AU - Das, Yannick
AU - Swinkels, Daniëlle
AU - Kocherlakota, Sai
AU - Vinckier, Stefan
AU - Vaz, Frédéric M.
AU - Wever, Eric
AU - van Kampen, Antoine H. C.
AU - Jun, Bokkyoo
AU - Do, Khanh V.
AU - Moons, Lieve
AU - Bazan, Nicolas G.
AU - van Veldhoven, Paul P.
AU - Baes, Myriam
N1 - Funding Information: We would like to thank Benno Das, An Carton and An Manderveld for the excellent technical assistance and the Genomics Core Leuven for the assistance in the RNA sequencing experiment. Funding. This research was supported by grants from the Belgian Fund for Research in Ophthalmology, from the KU Leuven (C14/18/088) and from the Research Foundation?Flanders (FWO G0A8619N). The Leica SP8? confocal microscope was provided by InfraMouse (KU Leuven-VIB) through a Hercules type 3 project (ZW09-03). Publisher Copyright: © Copyright © 2021 Das, Swinkels, Kocherlakota, Vinckier, Vaz, Wever, van Kampen, Jun, Do, Moons, Bazan, Van Veldhoven and Baes.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - 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.
AB - 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.
KW - DHA
KW - PUFA
KW - multifunctional protein 2
KW - peroxisome
KW - photoreceptors
KW - retina
KW - β-oxidation
UR - http://www.scopus.com/inward/record.url?scp=85100903902&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fcell.2021.632930
DO - https://doi.org/10.3389/fcell.2021.632930
M3 - Article
C2 - 33604342
SN - 2296-634X
VL - 9
JO - Frontiers in cell and developmental biology
JF - Frontiers in cell and developmental biology
M1 - 632930
ER -