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 Jr; 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

doi:10.1038/s41467-024-50500-z

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

Nat Commun. 2024 Jul 21;15(1):6150. doi: 10.1038/s41467-024-50500-z.

Authors

Sayan Ghosh¹, Ruchi Sharma², Sridhar Bammidi¹, Victoria Koontz¹, Mihir Nemani¹, Meysam Yazdankhah¹, Katarzyna M Kedziora³, Donna Beer Stolz³, Callen T Wallace³, Cheng Yu-Wei⁴, Jonathan Franks³, Devika Bose², Peng Shang⁵, Helena M Ambrosino⁵, James R Dutton⁶, Zhaohui Geng⁶, Jair Montford², Jiwon Ryu², Dhivyaa Rajasundaram⁷, Stacey Hose¹, José-Alain Sahel^{1

8}, Rosa Puertollano⁹, Toren Finkel⁴, J Samuel Zigler Jr¹⁰, Yuri Sergeev¹¹, Simon C Watkins³, Eric S Goetzman⁷, Deborah A Ferrington^{5

12}, Miguel Flores-Bellver¹³, Kai Kaarniranta^{14

15}, Akrit Sodhi¹⁰, Kapil Bharti¹⁶, James T Handa¹⁷, Debasish Sinha^{18

19}

Affiliations

¹ Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
³ Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ Doheny Eye Institute, Pasadena, CA, USA.
⁶ Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
⁷ Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Institut De La Vision, INSERM, CNRS, Sorbonne Université, Paris, France.
⁹ Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Protein Biochemistry & Molecular Modeling Group, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
¹² Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA, USA.
¹³ Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹⁴ Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹⁵ Department of Molecular Genetics, University of Lodz, Lodz, Poland.
¹⁶ Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
¹⁷ Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁸ Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
¹⁹ Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].

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.

MeSH terms

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

Substances

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

Abstract

MeSH terms

Substances

Grants and funding