bims-mideyd 2024-07-28 papers

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

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

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.

DOI: https://doi.org/10.1038/s41467-024-50500-z

Mol Metab. 2024 Jul 22. pii: S2212-8778(24)00126-1. [Epub ahead of print] 101995

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.

Allison Grenell, Charandeep Singh, Monisha Raju, Alyson Wolk, Sonal Dalvi, Geeng-Fu Jang, John S Crabb, Courtney E Hershberger, Kannan V Manian, Karen Hernandez, John W Crabb, Ruchira Singh, Jianhai Du, Bela Anand-Apte.

OBJECTIVES: Mutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. One major function of RPE is the synthesis and transport of vital nutrients, such as glucose, to the retina. Recently, metabolic dysfunction in RPE cells has emerged as an important contributing factor in retinal degenerations. We set out to determine if RPE metabolic dysfunction was contributing to SFD pathogenesis.
METHODS: Quantitative proteomics was conducted on RPE of mice expressing the S179C variant of TIMP3, known to be causative of SFD in humans. Proteins found to be differentially expressed (P<0.05) were analyzed using statistical overrepresentation analysis to determine enriched pathways, processes, and protein classes using g:profiler and PANTHER Gene Ontology. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. RPE metabolism was directly probed using isotopic tracing coupled with GC/MS analysis. Steady state [U-13C6] glucose isotopic tracing was preliminarily conducted on S179C ARPE-19 followed by [U-13C6] glucose and [U-13C5] glutamine isotopic tracing in SFD iRPE cells.
RESULTS: Quantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes. Notably these results highlighted dysregulated glycolysis and glucose metabolism. Stable isotope tracing experiments with [U-13C6] glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells. Similarly, [U-13C6] glucose tracing in SFD iRPE revealed increased glucose contribution to glycolysis and the TCA cycle. Additionally, [U-13C5] glutamine tracing found evidence of altered malic enzyme activity.
CONCLUSION: This study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.

Keywords: RPE; TIMP3; central carbon metabolism; isotopic tracer; retinal pigment epithelium metabolism

DOI: https://doi.org/10.1016/j.molmet.2024.101995

Mayo Clin Proc Innov Qual Outcomes. 2024 Aug;8(4): 364-374

Recent Updates on the Diagnosis and Management of Age-Related Macular Degeneration.

Nithya Boopathiraj, Isabella V Wagner, Syril K Dorairaj, Darby D Miller, Michael W Stewart.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the Western world, with a higher prevalence among Europeans and North Americans than that in Africans, Hispanics, and Asians. Advanced AMD is categorized as atrophic (dry) or exudative (wet/neovascular age-related macular degeneration [nAMD]). Dry AMD is characterized by progressive geographic atrophy of the retinal pigment epithelium and outer retinal layers, whereas nAMD is characterized by new vessels that invade the subretinal and/or subretinal pigment epithelium spaces. Existing treatments delay the onset of advanced AMD and reverses vision loss for a couple of years before atrophy usually decreases central visual acuity. We searched PubMed and Medline databases from January 1, 1980, to December 1, 2023, using the following search terms: macular degeneration, choroidal neovascularization, geographic atrophy, drusen, age-related maculopathy, AMD, ARMD, and anti-VEGF. Relevant articles in English (or English translations) were retrieved and reviewed. Bibliographies of the identified manuscripts were also reviewed to identify relevant studies. Age-related macular degeneration most commonly affects people older than 55 years. Visual prognosis varies, with advanced lesions (nAMD and geographic atrophy) leading to rapid, progressive loss of central vision and contrast sensitivity. Although AMD is not a life-threatening disease, reduced vision profoundly compromises quality of life and necessitates living assistance for many patients. Over the past 2 decades, advances in prevention (vitamin supplementation) and therapy (antivascular endothelial growth factor and complement inhibitor drugs) have reduced vision loss and blindness. Further research is needed to decrease the incidence of blindness in patients with advanced disease.

DOI: https://doi.org/10.1016/j.mayocpiqo.2024.05.003