bims-mideyd 2026-01-18 papers

Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2505412123

Molecular underpinnings of induced degenerative heterogeneity in the retinal pigment epithelium.

Krishna Kumar Singh, Yang Jin, Ming-Wen Hu, Isabella Palazzo, Marisol Cano, Thanh Hoang, Imran Bhutto, Shusheng Wang, Debasish Sinha, Seth Blackshaw, Jiang Qian, James T Handa.

Cigarette smoking induces epigenetic changes that can cause degenerative heterogeneity with aging and disease. In disease such as age-related macular degeneration (AMD), the leading worldwide cause of blindness among the elderly, retinal pigment epithelial (RPE) cell heterogeneity is a key change. Since smoking is a powerful risk factor for AMD, we hypothesized that smoke induces epigenetic-mediated degenerative RPE heterogeneity. We administered cigarette smoke condensate (CSC) to young and aged mice. Using snRNA-seq and single nuclear ATAC sequencing, we identified distinct healthy and dedifferentiated RPE clusters in both aged vehicle- and young CSC-treated mice. Dedifferentiated RPE had globally decreased chromatin accessibility and expression of genes linked to "hallmarks of aging." Notably, young, dedifferentiated RPE also exhibited a compensatory upregulation of hallmarks of aging-related genes including mitochondrial function and proteostasis while aged dedifferentiated RPE did not, which decreased their survival following CSC treatment, as experimentally verified with TUNEL labeling. Similar populations of dedifferentiated and healthy RPE were identified both in mice exposed to cigarette smoke for 4 mo and in macular RPE from a donor who smoked and another with early AMD, but not from a nonsmoker donor. Degenerative cellular heterogeneity that includes an abnormal cluster can jeopardize cell survival and represents a hallmark of ocular aging.

Keywords: age-related macular degeneration (AMD); aging; heterogeneity; retinal pigment epithelium (RPE); smoking

DOI: https://doi.org/10.1073/pnas.2505412123

Cell Rep. 2026 Jan 12. pii: S2211-1247(25)01586-4. [Epub ahead of print]45(1): 116814

Single-cell multiome and enhancer connectome of human retinal pigment epithelium and choroid nominate causal variants in macular degeneration.

Sean K Wang, Jiaying Li, Surag Nair, Reshma Kosaraju, Yun Chen, Yuanyuan Zhang, Anshul Kundaje, Yuwen Liu, Ningli Wang, Howard Y Chang.

Age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Genome-wide association studies (GWASs) of AMD have identified dozens of risk loci that may house disease targets. However, variants at these loci are largely noncoding, making it difficult to assess their function and whether they are causal. Here, we present a single-cell gene expression and chromatin accessibility atlas of human retinal pigment epithelium (RPE) and choroid to systematically analyze both coding and noncoding variants implicated in AMD. We employ HiChIP and activity-by-contact modeling to map enhancers in these tissues and predict cell and gene targets of risk variants. We further perform allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to functionally test variant activity in RPE cells, including in the context of complement activation. Our work nominates pathogenic variants and mechanisms in AMD and offers a rich and accessible resource for studying diseases of the RPE and choroid.

Keywords: CP: genomics; HiChIP; STARR-seq; age-related macular degeneration; choroid; epigenomics; multi-omics; retinal pigment epithelium; single-cell ATAC-seq; single-cell RNA-seq

DOI: https://doi.org/10.1016/j.celrep.2025.116814

bioRxiv. 2026 Jan 07. pii: 2026.01.06.697989. [Epub ahead of print]

Complement Factor H (Y402H) polymorphism for age-related macular degeneration alters retinal lipids.

Peng Shang, Johnson Hoang, Elise Hong, Zhaohui Geng, Helena Ambrosino, Eric Abnoosian, Xiaoyu Zhu, Min Ma, Nova A Wei-Navarro, Beau Webber, Jun Qu, Sandra R Montezuma, Martin-Paul Agbaga, James R Dutton, Deborah A Ferrington.

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is associated with multiple risk factors and involves death of the retinal pigment epithelium (RPE). We investigated how the Y402H polymorphism of Complement Factor H (CFH) and cigarette smoke extract (CSE), major AMD genetic and environmental risks, affect lipid metabolism in RPE differentiated from induced pluripotent stem cells (iPSC-RPE) that were derived from human donors genotyped for low-risk (LR) or high-risk (HR) CFH. Results from discovery-based (lipidomics, proteomics) and targeted (mitochondrial fatty acid oxidation (FAO)) assays found significant genotype-dependent differences under basal conditions include higher free fatty acids and cholesterol esters in HR cells. CSE induced differences in proteins regulating lipid handling, lipolysis, and inflammation. Lower FAO in HR cells was observed in multiple donors and pairs of parent/isogenic edited lines compared with LR lines. CSE induced lipid accumulation, lipid composition remodeling, and upregulation of proteins involved in lipid synthesis/hydrolysis, production of bioactive lipid mediators, and metabolism of ceramide and cholesterol. These results elucidate putative mechanisms driving pathology in RPE harboring CFH Y402H.

DOI: https://doi.org/10.64898/2026.01.06.697989

Invest Ophthalmol Vis Sci. 2026 Jan 05. 67(1): 4

Inhibition of Pathological Mitochondrial Fission in Retinal Pigment Epithelium Mitigates Choroidal Neovascularization.

Hiroto Yasuda, Shinsuke Nakamura, Aimi Shirakawa, Yoshiki Kuse, Masamitsu Shimazawa.

Purpose: Mitochondria are highly dynamic organelles that continuously undergo fission and fusion, and their dysfunction is associated with various age-related disorders. This study aimed to elucidate the role of mitochondrial fission in the development of choroidal neovascularization (CNV), a hallmark of neovascular age-related macular degeneration (AMD), and to evaluate the therapeutic potential of its pharmacological inhibition.
Methods: The murine CNV model was created by laser photocoagulation using C57BL/6J mice. Expression changes of mitochondrial fission-related protein during CNV development were examined using western blotting and immunofluorescence. To assess the effectiveness of pharmacological inhibition of mitochondrial fission, the effects of mitochondrial division inhibitor-1 (Mdivi-1) and mitochondrial fusion promoter (M1) were evaluated by CNV area measurement, fluorescein angiography, and western blot analysis. The pro-angiogenic mechanisms associated with mitochondrial fission were further investigated in RPE cells cultured under hypoxic condition.
Results: In a murine laser-induced CNV model, mitochondrial fission-related proteins increased in the retinal pigment epithelium (RPE)-choroid complex, and the high expression of phosphorylated dynamin-related protein 1 (DRP1) was observed in RPE cells surrounding the CNV lesion. Additionally, intravitreal injection of Mdivi-1 or M1 suppressed CNV formation, vascular leakage, and pro-angiogenic factor production. In RPE cells exposed to hypoxia, DRP1-mediated mitochondrial fission was rapidly activated, accompanied by increased mitochondrial reactive oxygen species production. Moreover, inhibition of mitochondrial fission suppressed mitochondrial bioenergetic dysfunction and the upregulation of vascular endothelial growth factor.
Conclusions: These findings support that pharmacological inhibition of activated mitochondrial fission could serve as a potential therapeutic approach for neovascular AMD.

DOI: https://doi.org/10.1167/iovs.67.1.4