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

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism Animals Proto-Oncogene Proteins c-akt / metabolism Sirtuins / metabolism Macular Degeneration / metabolism Humans Mice Retinal Pigment Epithelium / metabolism Lysosomes / metabolism Signal Transduction Autophagy Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism Mice, Inbred C57BL Mitochondria / metabolism Disease Models, Animal Induced Pluripotent Stem Cells / metabolism Male

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
21 Jul 2024
Historique:
received: 18 08 2023
accepted: 10 07 2024
medline: 22 7 2024
pubmed: 22 7 2024
entrez: 21 7 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-50500-z PMID: 39034314
pubmed: 39034314
doi: 10.1038/s41467-024-50500-z
pii: 10.1038/s41467-024-50500-z
doi:

Substances chimiques

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors 0
Proto-Oncogene Proteins c-akt EC 2.7.11.1
Sirtuins EC 3.5.1.-
Akt2 protein, mouse EC 2.7.11.1
Tcfeb protein, mouse 0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha 0
SIRT5 protein, mouse 0
Ppargc1a protein, mouse 0
AKT2 protein, human EC 2.7.11.1
SIRT5 protein, human EC 3.5.1.-
TFEB protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

6150

Subventions

Organisme : NEI NIH HHS
ID : R01 EY031594
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY032516
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028554
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028554
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY031594
Pays : United States
Organisme : BrightFocus Foundation (BrightFocus)
ID : Postdoctoral Fellowship on Macular Degeneration
Organisme : Academy of Finland (Suomen Akatemia)
ID : 333302

Informations de copyright

© 2024. The Author(s).

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Auteurs

Sayan Ghosh (S)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Ruchi Sharma (R)

Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Sridhar Bammidi (S)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Victoria Koontz (V)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Mihir Nemani (M)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Meysam Yazdankhah (M)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Katarzyna M Kedziora (KM)

Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Donna Beer Stolz (DB)

Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Callen T Wallace (CT)

Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
ORCID: 0000-0001-6852-4976

Cheng Yu-Wei (C)

Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
ORCID: 0000-0001-8973-1253

Jonathan Franks (J)

Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Devika Bose (D)

Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Peng Shang (P)

Doheny Eye Institute, Pasadena, CA, USA.

Helena M Ambrosino (HM)

Doheny Eye Institute, Pasadena, CA, USA.

James R Dutton (JR)

Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Zhaohui Geng (Z)

Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Jair Montford (J)

Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Jiwon Ryu (J)

Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
ORCID: 0000-0003-0251-7858

Dhivyaa Rajasundaram (D)

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Stacey Hose (S)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

José-Alain Sahel (JA)

Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Institut De La Vision, INSERM, CNRS, Sorbonne Université, Paris, France.
ORCID: 0000-0002-4831-1153

Rosa Puertollano (R)

Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Toren Finkel (T)

Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
ORCID: 0000-0002-0726-3546

J Samuel Zigler (JS)

Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Yuri Sergeev (Y)

Protein Biochemistry & Molecular Modeling Group, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
ORCID: 0000-0002-7204-6572

Simon C Watkins (SC)

Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
ORCID: 0000-0003-4092-1552

Eric S Goetzman (ES)

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Deborah A Ferrington (DA)

Doheny Eye Institute, Pasadena, CA, USA.
Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA, USA.

Miguel Flores-Bellver (M)

Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
ORCID: 0000-0003-3421-3699

Kai Kaarniranta (K)

Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Department of Molecular Genetics, University of Lodz, Lodz, Poland.

Akrit Sodhi (A)

Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0000-0001-5441-1014

Kapil Bharti (K)

Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. kapil.bharti@nih.gov.

James T Handa (JT)

Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. jthanda@jhmi.edu.
ORCID: 0000-0003-1314-1745

Debasish 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.
ORCID: 0000-0002-1739-5577

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Eucaryotes › Animaux › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Sirtuines › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Maladies de l'oeil › Rétinopathies › Dégénérescence de la rétine › Dégénérescence maculaire › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Organes des sens › Oeil › Rétine › Épithélium pigmentaire de la rétine › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Lysosomes › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Autophagie › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Coactivateurs de récepteurs nucléaires › Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › The AKT2/SIRT5/TFEB pathway as a potential...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › The AKT2/SIRT5/TFEB pathway as a potential...