bims-mideyd 2026-07-12 papers

Neurobiol Aging. 2026 Jul 06. pii: S0197-4580(26)00123-5. [Epub ahead of print]168 1-13

Exogenous mitochondrial transplantation attenuates oxidative stress-driven retinal degeneration in a sodium iodate - induced mouse model.

Seok Jae Lee, Sung-Eun Noh, Jeong Hun Kim.

Age-related macular degeneration (AMD) is a degenerative retinal disease initiated by dysfunction of the retinal pigment epithelium (RPE), in which age-related mitochondrial impairment, oxidative stress, chronic inflammation, and complement activation collectively drive outer retinal dysfunction and RPE atrophy, ultimately leading to progressive central vision loss. Accumulating evidence indicates that mitochondrial abnormalities, including excessive reactive oxygen species (ROS) production, mitochondrial fragmentation, and inflammatory signaling, play a central role in AMD pathogenesis. In this study, we investigated the therapeutic potential of exogenous mitochondrial transplantation using a sodium iodate (SI)-induced retinal degeneration model that recapitulates key pathological features of dry AMD. In ARPE-19 cells, SI-induced oxidative stress triggered mitochondrial fragmentation, inflammasome activation, and tight junction disruption, whereas delivery of mitochondria isolated from bone marrow-derived mesenchymal stem cells attenuated mitochondrial dysfunction and preserved RPE barrier integrity by suppressing oxidative and inflammatory signaling. Consistent with these in vitro findings, intravitreal mitochondrial transplantation in SI-treated mice attenuated RPE shedding/migration and outer nuclear layer disorganization while suppressing retinal oxidative stress, inflammatory cytokine expression, and complement activation. Importantly, mitochondrial transplantation mitigated the decline in retinal function, as assessed by electroretinography and optokinetic response testing, without fully restoring responses to control levels. Collectively, these results support exogenous mitochondrial transplantation as a promising cell-free therapeutic strategy to attenuate oxidative stress-driven retinal degeneration by modulating mitochondrial dysfunction and associated inflammatory pathways in AMD.

Keywords: Age-related macular degeneration; Bone marrow–derived mesenchymal stem cells; Mitochondrial dysfunction; Outer retinal degeneration; Retinal aging; Retinal pigment epithelium

DOI: https://doi.org/10.1016/j.neurobiolaging.2026.07.002

Autophagy. 2026 Jul 10. 1-21

Targeting the SNAI1-LAMP3 axis to restore lysosomal function and alleviate autophagic flux impairment to delay retinal degeneration.

Yuke Ji, Yanan Sun, Xiaosheng Huang, Jia Liang, Dong Fang, Weihua Yang, Lujia Feng, Shaochong Zhang.

Retinal degenerative diseases are a leading cause of irreversible blindness. Their pathogenesis is intricately linked to oxidative stress-induced dysfunction of retinal pigment epithelial (RPE) cells and subsequent retinal degeneration. Macroautophagy/autophagy, a critical cellular degradation pathway, plays a vital role in maintaining RPE homeostasis, yet its dysregulation in retinal degenerative diseases remains poorly understood. In this study, we observed that sodium iodate (NaIO3), an oxidative stress inducer, triggered lysosomal dysfunction via lysosomal membrane permeabilization (LMP), thereby impairing autophagic flux in RPE cells and exacerbating retinal degeneration. RNA sequencing identified LAMP3 (lysosomal-associated membrane protein 3) as a downregulated gene following NaIO3 treatment. Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment. Furthermore, upregulation of LAMP3 reduced oxidative stress and apoptosis in RPE cells, while alleviating retinal degeneration in a NaIO3-induced mouse model. Mechanistically, our data suggested that NaIO3 upregulated the transcription factor SNAI1, which acts as a transcriptional repressor of LAMP3. SNAI1 knockdown increased LAMP3 expression, thereby facilitating the recovery of lysosomal function and the alleviation of autophagic impairment. Collectively, our findings indicate that the SNAI1-LAMP3 axis contributes to the regulation of the autophagy-lysosomal pathway in retinal degeneration, highlighting a potential therapeutic target for delaying disease progression.Abbreviations: AMD: age-related macular degeneration; AO: acridine orange; Baf A1: bafilomycin A1; BAX: BCL2-associated X protein; BCL2: B cell leukemia/lymphoma 2; BSA: bovine serum albumin; CCK-8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DHE: dihydroethidium; EdU: 5-ethynyl-2'-deoxyuridine; ERG: electroretinography; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HsRPE: human primary retinal pigment epithelial; JC-1: 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; LAMP3: lysosomal-associated membrane protein 3; LGALS3: lectin, galactose binding, soluble 3; LLOMe: leu-leu methyl ester; LMP: lysosomal membrane permeabilization; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NAC: N-acetyl-L-cysteine; NaIO3: sodium iodte; NC: negative control; OCT: optical coherence tomography; PCA: principal component analysis; PI: propidium iodide; qRT-PCR: quantitative real-time polymerase chain reaction; Rapa: rapamycin; ROS: reactive oxygen species; RP: retinitis pigmentosa; RPE: retinal pigment epithelium; RPE65: retinal pigment epithelium 65; siRNA: small interfering RNA; SNAI1: snail family zinc finger 1; SQSTM1/p62: sequestosome 1; TJP1/ZO-1: tight junction protein 1; ZNF135: zinc finger protein 135.

Keywords: Autophagy; LAMP3; SNAI1; lysosomal membrane permeabilization; retinal degeneration

DOI: https://doi.org/10.1080/15548627.2026.2700025

Transl Vis Sci Technol. 2026 Jul 01. 15(7): 12

Characterization of Rcbtb1 Knockout Mice and Evaluation of AAV2-RCBTB1 Gene Replacement Therapy.

Samuel McLenachan, Rabab Rashwan, Zhiqin Huang, Sang Yoon Moon, Khine Zaw, Caitlin R Hannan, Slavica Pervan, Dan Zhang, Lisa Griffiths, Livia S Carvalho, Fred K Chen.

Purpose: Biallelic pathogenic variants in the RCC1 and BTB domain-containing protein 1 (RCBTB1) gene cause an adult-onset retinal dystrophy. Here, we generated a knockout mouse model of RCBTB1 deficiency for the evaluation of RCBTB1 gene therapy.
Methods: Rcbtb1-knockout (KO) mice were generated with a homozygous deletion removing exons 2 and 3 of Rcbtb1. Wild-type (WT) and Rcbtb1-KO mice were assessed by optical coherence tomography and electroretinography at 3, 8, and 14 months of age. Retinal ultrastructure was assessed by transmission electron microscopy. Subretinal injections of adeno-associated virus 2 (AAV2)-RCBTB1 or AAV2-enhanced green fluorescent protein (EGFP) vector were performed at 2 months, and mice were analyzed at 8 months. Retinal gene expression was assessed by quantitative PCR and immunohistochemistry.
Results: Retinal Rcbtb1 expression was absent in Rcbtb1-KO mice. Eight-month-old Rcbtb1-KO mice showed reduced outer retinal thickness compared with WT mice. Ultrastructural analysis demonstrated increased mitochondrial damage in retinal pigment epithelial cells and increased frequencies of mitochondria with oxidative inclusions in photoreceptor inner segments in 8-month-old Rcbtb1-KO mice. Degenerating retinal pigment epithelium (RPE) and photoreceptors were observed in Rcbtb1-KO mice. Bruch's membrane appeared thicker in Rcbtb1-KO mice and contained druse-like deposits. Treatment with AAV2-RCBTB1 induced sustained RCBTB1 expression and preserved outer retinal thickness in 8-month-old Rcbtb1-KO mice.
Conclusions: Rcbtb1-KO mice showed accelerated outer retinal thinning, increased mitochondrial damage in the RPE, and photoreceptor apoptosis. AAV2-RCBTB1 vectors induced long-term retinal expression of RCBTB1 and prevented retinal thinning in Rcbtb1-KO mice.
Translational Relevance: Rcbtb1-KO mice provide a useful animal model for modeling RCBTB1 deficiency and preclinical screening of novel treatments.

DOI: https://doi.org/10.1167/tvst.15.7.12

J Clin Invest. 2026 Jul 07. pii: e191272. [Epub ahead of print]

A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated Caspase-1 inhibition.

Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identifies a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the understanding of the heterogeneity of degenerative RPE cells. Specifically, omics analyses in human and macaque RPE reveal a peripheral RPE cell population with high SERPINE3 expression, while SERPINE3-GFP knock-in mice show comparable expression patterns. In addition, SMART-seq2 analysis further distinguishes transcriptomic profiles between GFP-positive and GFP-negative RPE cells. Under oxidative stress, SERPINE3 expression increases, and GFP-positive cells exhibit improved survival and reentry into the cell cycle. Notably, genetic studies indicate that SERPINE3 is essential for the oxidative stress resistance of GFP-positive cells. Moreover, loss of SERPINE3 results in regional RPE degeneration and increased microglial accumulation in aged mice. Mechanistically, proteinase screening and co-immunoprecipitation indicate that SERPINE3 targets Caspase-1. Importantly, delivery of SERPINE3 via AAV-Serpine3 partially reduces RPE degeneration in an oxidative damage model. These findings advance the understanding of RPE heterogeneous degeneration and highlight SERPINE3 as a protective factor with therapeutic potential for macular atrophy.

Keywords: Cell biology; Ophthalmology; Retinopathy

DOI: https://doi.org/10.1172/JCI191272

Biosci Rep. 2026 Jul 22. pii: BSR20250121. [Epub ahead of print]46(7):

Mechanistic insights into the role of PEDF-R (PNPLA2) in photoreceptors.

S Patricia Becerra.

Photoreceptors are highly specialized neurons that depend on continuous membrane renewal and tightly regulated lipid homeostasis to maintain their visual function. Age-associated disruptions of these processes increase cellular stress and contribute to photoreceptor degeneration. Pigment epithelium-derived factor (PEDF) is a potent neuroprotective factor in the retina, and the identification of its receptor, PEDF-R (PNPLA2), has provided key mechanistic insight into how PEDF signaling is coupled to lipid metabolism. The present review examines the molecular and cellular mechanisms underlying PEDF-R function in photoreceptors and the retinal pigment epithelium (RPE). PEDF-R acts as a multifunctional enzyme with phospholipase and lipase activities that link extracellular PEDF binding to intracellular lipid remodeling. Through these activities, PEDF-R has been associated with processes essential for photoreceptor survival such as membrane phospholipid turnover, mitochondrial integrity, calcium homeostasis, and redox balance. In addition, PEDF-R contributes to retinoid metabolism and lipid processing associated with outer-segment renewal in the RPE. We further discuss how disruption of the PEDF-PEDF-R pathway impairs lipid homeostasis, promotes oxidative and inflammatory stress, and increases susceptibility to age-related retinal degeneration. These insights position PEDF-R as a key contributor to photoreceptor homeostasis and a potential therapeutic target for preserving retinal function in aging and disease.

Keywords: PEDF-R; PNPLA2; lipids; neuroprotection; phospholipases; photoreceptors

DOI: https://doi.org/10.1042/BSR20250121

Invest Ophthalmol Vis Sci. 2026 Jul 01. 67(8): 13

The Molecular Basis of Ocular Aging: Mechanisms, Pathologies, and Emerging Therapeutics.

Yuan Zong, Qiwei Fan, Shuang Qiu, Huang Zhang, Zhimin Cen.

Age-related eye diseases (AREDs)-including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy-are leading causes of permanent blindness. Current treatments manage clinical manifestations but do not halt the molecular processes that drive disease progression. This limitation has shifted attention toward "geroscience," a strategy that targets the fundamental biology of aging rather than treating each disease in isolation. Four key hallmarks of aging-mitochondrial dysfunction, loss of proteostasis, cellular senescence, and epigenetic drift-are widely implicated in AREDs. We review evidence that these hallmarks do not act independently; instead, they form an interactive, self-reinforcing network. The way this network engages differs from tissue to tissue. In the high-energy environment of the retinal pigment epithelium, mitochondrial dysfunction dominates and drives AMD. In the mechanically stressed trabecular meshwork (TM), senescence and epigenetic drift take precedence, leading to glaucoma. In the neurovascular unit, chronic hyperglycemia routes the same network into a metabolic-epigenetic amplification loop that sustains diabetic retinopathy. The same aging mechanisms, routed through distinct tissue contexts, thus produce divergent clinical phenotypes. We also evaluate emerging therapies, including senolytics, mitochondria-targeted agents, and partial epigenetic reprogramming, and identify key intervention nodes such as NLRP3, p62, and NAD⁺ metabolism. Dismantling these pathological feedback loops offers a path beyond symptom management toward combination strategies that restore tissue resilience.

DOI: https://doi.org/10.1167/iovs.67.8.13