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Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model

1
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, 70211 Kuopio, Finland
2
Faculty of Medicine, Department of Anatomy, Histology and Embryology, University of Debrecen, Medical and Health Science Centre, Nagyerdei krt. 98, H-4032 Debrecen, Hungary
3
Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland
4
Institute of Dentistry and Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
5
Department of Ophthalmology and Kuopio University Hospital, University of Eastern Finland, 70029 Kuopio, Finland
*
Author to whom correspondence should be addressed.
These authors contribute equally to this work.
Int. J. Mol. Sci. 2020, 21(6), 1976; https://doi.org/10.3390/ijms21061976
Received: 12 February 2020 / Revised: 9 March 2020 / Accepted: 12 March 2020 / Published: 13 March 2020
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
Increased oxidative stress and mitochondrial damage are observed in protein aggregation diseases, such as age-related macular degeneration (AMD). We have recently reported elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in the retinal pigment epithelial cells (RPE) of the dry AMD-resembling NFE2L2/PGC1α double knockout (dKO) mouse model. Here, we provide evidence of a disturbance in the autolysosomal machinery handling mitochondrial clearance in the RPE cells of one-year-old NFE2L2/PGC1α-deficient mice. Confocal immunohistochemical analysis revealed an upregulation of autophagosome marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) as well as numerous mitophagy markers, such as PTE-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN) together with damaged mitochondria. However, we detected no evidence of increased autolysosome formation in transmission electron micrographs or of colocalization of lysosomal marker LAMP2 (lysosome-associated membrane protein 2) and the mitochondrial marker ATP synthase β in confocal micrographs. Interestingly, we observed an upregulation of late autolysosomal fusion Ras-related protein (Rab7) in the perinuclear space of RPE cells together with autofluorescence aggregates. Our results reveal that there is at least a relative decrease of mitophagy in the RPE cells of NFE2L2/PGC1α dKO mice. This further supports the hypothesis that mitophagy is a putative therapy target in AMD-like pathology. View Full-Text
Keywords: ageing; oxidative stress; mitochondrial damage; age-related macular disease; mitophagy; autolysosomal fusion; protein aggregates ageing; oxidative stress; mitochondrial damage; age-related macular disease; mitophagy; autolysosomal fusion; protein aggregates
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Sridevi Gurubaran, I.; Viiri, J.; Koskela, A.; Hyttinen, J.M.; Paterno, J.J.; Kis, G.; Antal, M.; Urtti, A.; Kauppinen, A.; Felszeghy, S.; Kaarniranta, K. Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model. Int. J. Mol. Sci. 2020, 21, 1976.

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