TY - JOUR
T1 - The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD
AU - Ghosh, Sayan
AU - Sharma, Ruchi
AU - Bammidi, Sridhar
AU - Koontz, Victoria
AU - Nemani, Mihir
AU - Yazdankhah, Meysam
AU - Kedziora, Katarzyna M.
AU - Stolz, Donna Beer
AU - Wallace, Callen T.
AU - Yu-Wei, Cheng
AU - Franks, Jonathan
AU - Bose, Devika
AU - Shang, Peng
AU - Ambrosino, Helena M.
AU - Dutton, James R.
AU - Geng, Zhaohui
AU - Montford, Jair
AU - Ryu, Jiwon
AU - Rajasundaram, Dhivyaa
AU - Hose, Stacey
AU - Sahel, José Alain
AU - Puertollano, Rosa
AU - Finkel, Toren
AU - Zigler, J. Samuel
AU - Sergeev, Yuri
AU - Watkins, Simon C.
AU - Goetzman, Eric S.
AU - Ferrington, Deborah A.
AU - Flores-Bellver, Miguel
AU - Kaarniranta, Kai
AU - Sodhi, Akrit
AU - Bharti, Kapil
AU - Handa, James T.
AU - Sinha, Debasish
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85199218659&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85199218659&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-50500-z
DO - 10.1038/s41467-024-50500-z
M3 - Article
C2 - 39034314
AN - SCOPUS:85199218659
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6150
ER -