Nature Communications (Jul 2024)
The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD
- Sayan Ghosh,
- Ruchi Sharma,
- Sridhar Bammidi,
- Victoria Koontz,
- Mihir Nemani,
- Meysam Yazdankhah,
- Katarzyna M. Kedziora,
- Donna Beer Stolz,
- Callen T. Wallace,
- Cheng Yu-Wei,
- Jonathan Franks,
- Devika Bose,
- Peng Shang,
- Helena M. Ambrosino,
- James R. Dutton,
- Zhaohui Geng,
- Jair Montford,
- Jiwon Ryu,
- Dhivyaa Rajasundaram,
- Stacey Hose,
- José-Alain Sahel,
- Rosa Puertollano,
- Toren Finkel,
- J. Samuel Zigler,
- Yuri Sergeev,
- Simon C. Watkins,
- Eric S. Goetzman,
- Deborah A. Ferrington,
- Miguel Flores-Bellver,
- Kai Kaarniranta,
- Akrit Sodhi,
- Kapil Bharti,
- James T. Handa,
- Debasish Sinha
Affiliations
- Sayan Ghosh
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- Ruchi Sharma
- Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health
- Sridhar Bammidi
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- Victoria Koontz
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- Mihir Nemani
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- Meysam Yazdankhah
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- Katarzyna M. Kedziora
- Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine
- Donna Beer Stolz
- Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine
- Callen T. Wallace
- Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine
- Cheng Yu-Wei
- Aging Institute, University of Pittsburgh School of Medicine
- Jonathan Franks
- Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine
- Devika Bose
- Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health
- Peng Shang
- Doheny Eye Institute
- Helena M. Ambrosino
- Doheny Eye Institute
- James R. Dutton
- Stem Cell Institute, University of Minnesota
- Zhaohui Geng
- Stem Cell Institute, University of Minnesota
- Jair Montford
- Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health
- Jiwon Ryu
- Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health
- Dhivyaa Rajasundaram
- Department of Pediatrics, University of Pittsburgh School of Medicine
- Stacey Hose
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- José-Alain Sahel
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- Rosa Puertollano
- Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health
- Toren Finkel
- Aging Institute, University of Pittsburgh School of Medicine
- J. Samuel Zigler
- Wilmer Eye Institute, The Johns Hopkins University School of Medicine
- Yuri Sergeev
- Protein Biochemistry & Molecular Modeling Group, National Eye Institute, National Institutes of Health
- Simon C. Watkins
- Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine
- Eric S. Goetzman
- Department of Pediatrics, University of Pittsburgh School of Medicine
- Deborah A. Ferrington
- Doheny Eye Institute
- Miguel Flores-Bellver
- Department of Ophthalmology, University of Colorado Anschutz Medical Campus
- Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital
- Akrit Sodhi
- Wilmer Eye Institute, The Johns Hopkins University School of Medicine
- Kapil Bharti
- Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health
- James T. Handa
- Wilmer Eye Institute, The Johns Hopkins University School of Medicine
- Debasish Sinha
- Department of Ophthalmology, University of Pittsburgh School of Medicine
- DOI
- https://doi.org/10.1038/s41467-024-50500-z
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 18
Abstract
Abstract 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.
