TY - JOUR
T1 - The murine retinal pigment epithelium requires peroxisomal β-oxidation to maintain lysosomal function and prevent dedifferentiation
AU - Kocherlakota, Sai
AU - Das, Yannick
AU - Swinkels, Daniëlle
AU - Vanmunster, Maarten
AU - Callens, Manon
AU - Vinckier, Stefan
AU - Vaz, Frédéric M.
AU - Sinha, Debasish
AU - van Veldhoven, Paul P.
AU - Fransen, Marc
AU - Baes, Myriam
N1 - Funding Information: ACKNOWLEDGMENTS. We thank Elena Nefyodova, Benno Das, An Carton, and Ann Manderveld for their excellent technical assistance; Joshua Dunaief, University of Pennsylvania for the Best1-Cre mice; Nancy Philp,Thomas Jefferson University for sharing MCT1 and MCT3 antibodies, the metabolomics expertise core, Leuven for assistance with the metabolomics analysis and Peter Carmeliet, Vlaams Instituut voor Biotechnologie - Katholieke Universiteit Leuven, for his critical assessment of the manuscript. This work was supported by grants from the Flanders Research Foundation (FWO-Vlaanderen, FWO G0A8619N) and KU Leuven (C14/18/088). Funding Information: We thank Elena Nefyodova, Benno Das, An Carton, and Ann Manderveld for their excellent technical assistance; Joshua Dunaief, University of Pennsylvania for the Best1-Cre mice; Nancy Philp, Thomas Jefferson University for sharing MCT1 and MCT3 antibodies, the metabolomics expertise core, Leuven for assistance with the metabolomics analysis and Peter Carmeliet, Vlaams Instituut voor Biotechnologie - Katholieke Universiteit Leuven, for his critical assessment of the manuscript. This work was supported by grants from the Flanders Research Foundation (FWO-Vlaanderen, FWO G0A8619N) and KU Leuven (C14/18/088). Publisher Copyright: Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023
Y1 - 2023
N2 - Retinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but the mechanisms involved in the digestion and recycling of POS lipids are poorly understood. Although it was frequently assumed that peroxisomes may play an essential role, this was never investigated. Here, we show that global as well as RPE-selective loss of peroxisomal β-oxidation in multifunctional protein 2 (MFP2) knockout mice impairs the digestive function of lysosomes in the RPE at a very early age, followed by RPE degeneration. This was accompanied by prolonged mammalian target of rapamycin activation, lipid deregulation, and mitochondrial structural anomalies without, however, causing oxidative stress or energy shortage. The RPE degeneration caused secondary photoreceptor death. Notably, the deterioration of the RPE did not occur in an Mfp2/rd1 mutant mouse line, characterized by absent POS shedding. Our findings prove that peroxisomal β-oxidation in the RPE is essential for handling the polyunsaturated fatty acids present in ingested POS and shed light on retinopathy in patients with peroxisomal disorders. Our data also have implications for gene therapy development as they highlight the importance of targeting the RPE in addition to the photoreceptor cells.
AB - Retinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but the mechanisms involved in the digestion and recycling of POS lipids are poorly understood. Although it was frequently assumed that peroxisomes may play an essential role, this was never investigated. Here, we show that global as well as RPE-selective loss of peroxisomal β-oxidation in multifunctional protein 2 (MFP2) knockout mice impairs the digestive function of lysosomes in the RPE at a very early age, followed by RPE degeneration. This was accompanied by prolonged mammalian target of rapamycin activation, lipid deregulation, and mitochondrial structural anomalies without, however, causing oxidative stress or energy shortage. The RPE degeneration caused secondary photoreceptor death. Notably, the deterioration of the RPE did not occur in an Mfp2/rd1 mutant mouse line, characterized by absent POS shedding. Our findings prove that peroxisomal β-oxidation in the RPE is essential for handling the polyunsaturated fatty acids present in ingested POS and shed light on retinopathy in patients with peroxisomal disorders. Our data also have implications for gene therapy development as they highlight the importance of targeting the RPE in addition to the photoreceptor cells.
KW - lipids
KW - lysosomes
KW - peroxisomes
KW - retinal degeneration
KW - retinal pigment epithelium
UR - http://www.scopus.com/inward/record.url?scp=85175043307&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.2301733120
DO - https://doi.org/10.1073/pnas.2301733120
M3 - Article
C2 - 37862382
SN - 0027-8424
VL - 120
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 43
M1 - e2301733120
ER -