Nat Commun. 2024 Jul 21. 15(1): 6150
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.
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.