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 () and Debasish Sinha ()
Additional contact information
Sayan Ghosh: University of Pittsburgh School of Medicine
Ruchi Sharma: National Institutes of Health
Sridhar Bammidi: University of Pittsburgh School of Medicine
Victoria Koontz: University of Pittsburgh School of Medicine
Mihir Nemani: University of Pittsburgh School of Medicine
Meysam Yazdankhah: University of Pittsburgh School of Medicine
Katarzyna M. Kedziora: University of Pittsburgh School of Medicine
Donna Beer Stolz: University of Pittsburgh School of Medicine
Callen T. Wallace: University of Pittsburgh School of Medicine
Cheng Yu-Wei: University of Pittsburgh School of Medicine
Jonathan Franks: University of Pittsburgh School of Medicine
Devika Bose: National Institutes of Health
Peng Shang: Doheny Eye Institute
Helena M. Ambrosino: Doheny Eye Institute
James R. Dutton: University of Minnesota
Zhaohui Geng: University of Minnesota
Jair Montford: National Institutes of Health
Jiwon Ryu: National Institutes of Health
Dhivyaa Rajasundaram: University of Pittsburgh School of Medicine
Stacey Hose: University of Pittsburgh School of Medicine
José-Alain Sahel: University of Pittsburgh School of Medicine
Rosa Puertollano: National Institutes of Health
Toren Finkel: University of Pittsburgh School of Medicine
J. Samuel Zigler: The Johns Hopkins University School of Medicine
Yuri Sergeev: National Institutes of Health
Simon C. Watkins: University of Pittsburgh School of Medicine
Eric S. Goetzman: University of Pittsburgh School of Medicine
Deborah A. Ferrington: Doheny Eye Institute
Miguel Flores-Bellver: University of Colorado Anschutz Medical Campus
Kai Kaarniranta: University of Eastern Finland and Kuopio University Hospital
Akrit Sodhi: The Johns Hopkins University School of Medicine
Kapil Bharti: National Institutes of Health
James T. Handa: The Johns Hopkins University School of Medicine
Debasish Sinha: University of Pittsburgh School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50500-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50500-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50500-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().