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The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.

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Τίτλος: The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
Συγγραφείς: Ghosh S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Sharma R; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Bammidi S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Koontz V; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Nemani M; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Yazdankhah M; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Kedziora KM; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Stolz DB; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Wallace CT; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Yu-Wei C; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Franks J; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Bose D; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Shang P; Doheny Eye Institute, Pasadena, CA, USA., Ambrosino HM; Doheny Eye Institute, Pasadena, CA, USA., Dutton JR; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA., Geng Z; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA., Montford J; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Ryu J; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Rajasundaram D; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Hose S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Sahel JA; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Institut De La Vision, INSERM, CNRS, Sorbonne Université, Paris, France., Puertollano R; Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Finkel T; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Zigler JS Jr; Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Sergeev Y; Protein Biochemistry & Molecular Modeling Group, National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Watkins SC; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Goetzman ES; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Ferrington DA; Doheny Eye Institute, Pasadena, CA, USA.; Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA, USA., Flores-Bellver M; Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA., Kaarniranta K; Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.; Department of Molecular Genetics, University of Lodz, Lodz, Poland., Sodhi A; Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Bharti K; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. kapil.bharti@nih.gov., Handa JT; Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. jthanda@jhmi.edu., Sinha D; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Debasish@pitt.edu.; Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Debasish@pitt.edu.
Πηγή: Nature communications [Nat Commun] 2024 Jul 21; Vol. 15 (1), pp. 6150. Date of Electronic Publication: 2024 Jul 21.
Τύπος έκδοσης: Journal Article; Research Support, N.I.H., Extramural
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
Ιατρικοί όροι (MeSH): Basic Helix-Loop-Helix Leucine Zipper Transcription Factors*/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors*/genetics , Proto-Oncogene Proteins c-akt*/metabolism , Sirtuins*/metabolism , Sirtuins*/genetics , Macular Degeneration*/metabolism , Macular Degeneration*/pathology , Macular Degeneration*/genetics , Retinal Pigment Epithelium*/metabolism , Retinal Pigment Epithelium*/pathology , Lysosomes*/metabolism , Signal Transduction* , Autophagy*, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics ; Mitochondria/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Animals ; Humans ; Mice ; Mice, Inbred C57BL ; Disease Models, Animal ; Male
Περίληψη: Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.
(© 2024. The Author(s).)
Σχόλια: Update of: bioRxiv. 2023 Aug 09:2023.08.08.552343. doi: 10.1101/2023.08.08.552343.. (PMID: 37609254)
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Grant Information: R01 EY031594 United States EY NEI NIH HHS; 333302 Academy of Finland (Suomen Akatemia); R01 EY032516 United States EY NEI NIH HHS; U01 EY034669 United States EY NEI NIH HHS; P30 EY008098 United States EY NEI NIH HHS; Postdoctoral Fellowship on Macular Degeneration BrightFocus Foundation (BrightFocus); R01 EY028554 United States EY NEI NIH HHS
Molecular Sequence: GEO GSE269923
Substance Nomenclature: 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 3.5.1.- (Sirtuins)
EC 2.7.11.1 (Akt2 protein, mouse)
0 (Tcfeb protein, mouse)
0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
0 (SIRT5 protein, mouse)
0 (Ppargc1a protein, mouse)
EC 2.7.11.1 (AKT2 protein, human)
EC 3.5.1.- (SIRT5 protein, human)
0 (TFEB protein, human)
Entry Date(s): Date Created: 20240721 Date Completed: 20240721 Latest Revision: 20260717
Update Code: 20260718
PubMed Central ID: PMC11271488
DOI: 10.1038/s41467-024-50500-z
PMID: 39034314
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2041-1723
DOI:10.1038/s41467-024-50500-z