bims-mideyd 2026-08-16 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–08–16
six papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

LPA1-Induced EMT of Retinal Pigment Epithelial Cells Promotes Subretinal Fibrosis via USP1-Mediated Deubiquitination and Stabilization of ZEB1.
Off-Target Retinal Pigment Epithelium (RPE) Expression of Cre in the Rhodopsin-iCre75 Mouse Line.
AAV-NRF2 protects retinal and choroidal vasculature in a GDF15-dependent manner in an oxidative damage model of AMD.
Mitochondrial hOGG1-2a overexpression sensitizes HeLaS3 cells to oxidative stress, accompanied by mitochondrial dysfunction and reduced mtDNA integrity.
Smarcc1 drives optic stalk patterning and optic nerve head astrocyte differentiation.
Selective retinal neuron loss and impaired neurovascular support underlie myopic retinopathy in RPE-specific Lrp2-deficient mice.

Invest Ophthalmol Vis Sci. 2026 08 03. 67(10): 34

LPA1-Induced EMT of Retinal Pigment Epithelial Cells Promotes Subretinal Fibrosis via USP1-Mediated Deubiquitination and Stabilization of ZEB1.

Manhui Zhu, Liangning Cui, Yang Guo, Yuanyuan Tu, Yiyi Wang, Wanru Zhou, Yuting Zhang, Laiqing Xie, Haiying Jin.

Purpose: Subretinal fibrosis (SRF) is a vision-threatening complication of neovascular age-related macular degeneration (nAMD), yet effective antifibrotic strategies remain limited. This study investigated the role of lysophosphatidic acid receptor 1 (LPA1), a fibrosis-associated G protein-coupled receptor, in SRF progression and evaluated its therapeutic potential.
Methods: A two-stage laser injury model was used to induce SRF in C57BL/6J mice. LPA1 expression and its regulation of ubiquitin-specific peptidase 1 (USP1) and zinc finger E-box binding homeobox 1 (ZEB1) were assessed by western blotting and immunofluorescence. Retinal pigment epithelial (RPE) cell epithelial-mesenchymal transition (EMT) was evaluated by migration assays and fibrotic marker analysis. ZEB1 and USP1 loss-of-function experiments were performed to define their roles. Molecular docking and co-immunoprecipitation were used to examine USP1-mediated ZEB1 deubiquitination. The antifibrotic effects and the safety of LPA1 inhibition by BMS-986278 were assessed in vivo.
Results: LPA1 was upregulated in laser-induced SRF and was associated with increased fibrotic marker expression. LPA1 overexpression promoted RPE EMT and migration through the USP1/ZEB1 axis. Mechanistically, LPA1 increased USP1 expression, which stabilized ZEB1 and promoted its nuclear translocation by reducing ZEB1 ubiquitination. USP1 inhibition attenuated LPA1-induced EMT and fibrosis, similar to ZEB1 silencing. In vivo, BMS-986278 suppressed EMT and reduced SRF severity, with a stronger inhibitory effect on fibrotic lesions than on neovascular lesions.
Conclusions: LPA1 promotes SRF by driving RPE EMT through USP1-mediated deubiquitination and stabilization of ZEB1. Targeting the LPA1/USP1/ZEB1 axis may provide a promising therapeutic strategy for nAMD-associated SRF.

DOI: https://doi.org/10.1167/iovs.67.10.34
Invest Ophthalmol Vis Sci. 2026 08 03. 67(10): 28

Off-Target Retinal Pigment Epithelium (RPE) Expression of Cre in the Rhodopsin-iCre75 Mouse Line.

David G Ball, Eleanor Ostafin, William J Spencer.

Purpose: Cre mouse lines are an important tool to manipulate gene expression in specific cell types and at distinct developmental timepoints. Overlooked and off-target expression of Cre is a common issue with transgenic Cre lines that has confounded the interpretation of many studies. The rhodopsin-iCre75 mouse line expresses Cre behind a rod opsin promoter and has been the most widely used line for targeting rod photoreceptor cells over the past two decades. Here, we re-evaluated the specificity of the rhodopsin-iCre75 mouse line for rod photoreceptors.
Methods: We crossed the rhodopsin-iCre75 mouse line with the fluorescent Cre reporter strain, Ai14, which expresses tdTomato in Cre-lox recombined cells. We identified recombined cells in mouse eye tissues by confocal microscopy. Independent of this reporter strain and as validation, we detected the presence of Cre protein by western blotting.
Results: We report that Cre expression in the rhodopsin-iCre75 mouse line is unexpectedly not rod photoreceptor specific. We show that Cre is expressed in approximately 6% ± 2% (mean ± SD) of retinal pigment epithelium (RPE) cells by postnatal day 4, a timepoint preceding rhodopsin expression in rods. Recombined RPE cells are found in patches and are concentrated centrally where approximately 17% ± 6% (mean ± SD) of RPE cells are Cre positive.
Conclusions: These findings indicate that the rhodopsin-iCre75 line has unintended Cre recombination in RPE cells providing important implications for the interpretation of prior and future studies using this line.

DOI: https://doi.org/10.1167/iovs.67.10.28
Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2616985123

AAV-NRF2 protects retinal and choroidal vasculature in a GDF15-dependent manner in an oxidative damage model of AMD.

Shuai Wang, Sophia Zhao, Adam Daniels, Efrat Naaman, Apolonia Gardner, Lois E H Smith, Constance L Cepko.

  Oxidative stress is proposed to be a driver of age-related diseases. Age-related macular degeneration (AMD) is one such disease, where the retinal pigment epithelium (RPE) is affected early in the disease. Vasculature damage also occurs, sometimes preceding RPE damage. To model some aspects of dry AMD, we used the NaIO3 mouse model of oxidative damage. Disruption of the deep retinal vascular plexus, disorganization and death of capillaries within the choriocapillaris, and marked electroretinographic decline were observed. Adeno-associated virus (AAV) overexpressing the transcription factor, NRF2, which induces antioxidation enzymes and represses inflammation, was tested for protection of damage. The BEST1 promoter limited expression to the RPE. The RPE, photoreceptors, and vascular architecture in both retinal and choroidal compartments were protected. Conditioned medium from RPE-choroid explants, infected by AAV8/BEST1-NRF2, was sufficient to transfer partial protection in vivo, suggesting that NRF2 induces a protective secreted factor(s). Analysis of RNA-seq data nominated growth differentiation factor 15 (GDF15) as a candidate secreted mediator. Injection of recombinant GDF15 reproduced key protective phenotypes in vivo, whereas Gdf15 deficiency attenuated NRF2-mediated rescue. Pharmacologic inhibition of TGF-β receptor signaling diminished NRF2-induced protection, supporting involvement of this signaling pathway. In a laser-induced choroidal neovascularization model, intravitreal GDF15 injection reduced fluorescein leakage and lesion size. These findings support a model in which NRF2 activation in the RPE induces expression of GDF15, which is capable of protecting the RPE, photoreceptors, and the retinal and choroidal vasculature. NRF2 and GDF15 have therapeutic potential for ocular diseases, as well as for other diseases with vascular pathology.

Keywords:  GDF15; NRF2; choriocapillaris; retinal pigment epithelium; retinal vasculature

DOI:  https://doi.org/10.1073/pnas.2616985123
Free Radic Res. 2026 Aug 14. 1-29

Mitochondrial hOGG1-2a overexpression sensitizes HeLaS3 cells to oxidative stress, accompanied by mitochondrial dysfunction and reduced mtDNA integrity.

Weizhi Wang, Lanyun Yan, Fengxian Wu, Qiu-Mei Zhang-Akiyama.

  Mitochondria are essential organelles responsible for cellular ATP production and contain their own mitochondrial DNA (mtDNA), which encodes key components of oxidative phosphorylation. Because mitochondria continuously generate reactive oxygen species (ROS), mtDNA is particularly susceptible to oxidative damage. Although DNA repair enzymes are present in mitochondria, the regulation of mtDNA repair and its impact on cellular responses to oxidative stress remain incompletely understood. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme in the base excision repair (BER) pathway, and the mitochondrial isoform hOGG1-2a contributes to the maintenance of mtDNA integrity.In this study, HeLaS3 cell lines stably overexpressing hOGG1-2a were established to examine responses to oxidative stress. hOGG1-2a overexpression was associated with reduced survival following H2O2 treatment, γ-ray exposure, heat shock, and ultraviolet C (UVC) irradiation. Apoptotic cell death increased after oxidative stress. Mitochondrial membrane potential assessed by JC-1 staining was significantly reduced in hOGG1-2a-overexpressing cells. Long-range PCR analysis revealed reduced mtDNA amplification efficiency, and oxidative stress was accompanied by a greater reduction of the mitochondrial enzyme Aconitase 2. These cells exhibited elevated basal ATP levels and altered ATP responses under oxidative stress conditions. In addition, mitochondrial superoxide-associated fluorescence detected by MitoSOX™ was significantly increased.Combined long-range PCR and Sanger sequencing indicated reduced mtDNA amplification after H2O2 exposure without a marked increase in point mutations.Collectively, these findings suggest that hOGG1-2a overexpression sensitizes cells to oxidative stress and is associated with mitochondrial redox dysregulation, reduced mitochondrial membrane potential, altered ATP responses, and reduced mtDNA amplifiability during prolonged stress.

Keywords:  base excision repair; hOGG1-2a; mitochondrial DNA; mitochondrial alterations; mtDNA integrity; oxidative stress

DOI:  https://doi.org/10.1080/10715762.2026.2716701
Development. 2026 08 01. pii: dev205769. [Epub ahead of print]153(15):

Smarcc1 drives optic stalk patterning and optic nerve head astrocyte differentiation.

Nitay Zuk-Bar, Shai Ovadia, Guizhong Cui, Alexey Obolensky, Eyal Banin, Ron Ofri, Naihe Jing, Ruth Ashery-Padan.

  The optic nerve develops from the neuroectodermal optic stalk, which undergoes coordinated morphogenesis and gives rise to optic nerve astrocytes that support retinal ganglion cell axons. Here, we define the progression of astrocyte formation from the optic stalk and identify stage-specific functions of the SWI/SNF scaffolding subunits Smarcc1 and Smarcc2. Both factors are co-expressed in retinal pigment epithelium (RPE) and optic stalk progenitors, with Smarcc2 persisting in differentiated RPE and astrocytes. Conditional deletion using Dct-Cre revealed compensatory activity in pigmented lineages, whereas Smarcc1 loss uniquely disrupted optic nerve head morphogenesis, resulting in glial lamina collapse, retinal ganglion cell degeneration and progressive visual decline. Spatial transcriptomics and functional assays show that Smarcc1 enables dorsal optic stalk progenitors to transition from a pigmented, RPE-like state to astrocyte progenitors by repressing pigment gene programs and permitting Pax2 and Sox2 activity. After specification, Smarcc1 is also required for glial lamina assembly and astrocyte migration into the inner retina. These findings demonstrate that Smarcc1-dependent chromatin remodeling coordinates astrocyte specification with optic nerve head morphogenesis to maintain long-term retinal function.

Keywords:  Eye development; Mouse; Optic nerve head; Optic stalk; SWI/SNF

DOI:  https://doi.org/10.1242/dev.205769
Front Cell Neurosci. 2026 ;20 1856140

Selective retinal neuron loss and impaired neurovascular support underlie myopic retinopathy in RPE-specific Lrp2-deficient mice.

Jinyan Qi, Xuexue Cui, Caijiao Yi, Jian Liu, Wen Deng, Xiang-Ling Yuan, Yuanyuan Hu, Tong Wang, Heping Xu.

  Pathologic myopia is a major cause of irreversible visual impairment worldwide and is characterized by excessive axial elongation accompanied by progressive retinal degeneration. Whether vision loss results primarily from passive retinal stretching or selective neurodegeneration remains unclear, hindering the development of effective neuroprotective and regenerative therapies. Here, we investigated retinal neuronal, vascular, and glial alterations in retinal pigment epithelium (RPE)-specific Lrp2 knockout (Best1-Cre/Lrp2fl/fl conditional knockout, CKO) model of pathologic myopia. The CKO mice were examined longitudinally using multimodal ocular imaging, electroretinography, optokinetic testing, fluorescein angiography, and quantitative immunohistochemistry analysis. CKO phenotype+ mice developed early-onset, progressive axial elongation and high myopia, accompanied by fundus features closely resembling human pathologic myopia, including peripapillary and patchy chorioretinal atrophy. Retinal function was markedly impaired, with significant reductions in scotopic a-, b-, and c-wave amplitudes. Although axial elongation resulted in a 1.98-fold increase in retinal surface area and a 55.95% reduction in retinal thickness, quantitative correction for retinal expansion revealed selective neuronal loss rather than uniform retinal degeneration. Total numbers of rods, cones, horizontal cells, and GABAergic amacrine cells were reduced by 22, 40, 30, and 57%, respectively, together with a 66% loss of photoreceptor synaptic ribbons. In contrast, retinal ganglion cells and bipolar cells exhibited reduced density but preserved absolute cell numbers. These neuronal changes were accompanied by retinal and choroidal microvascular degeneration, Müller gliosis, microglial activation and subretinal accumulation, and RPE dysmorphology. Our findings demonstrate that axial elongation induces neuron subtype-specific degeneration rather than generalized retinal thinning. Our study identifies photoreceptors, horizontal cells, and inhibitory amacrine cells as particularly vulnerable populations and implicates impaired RPE support, neurovascular dysfunction, and chronic glial activation as key mechanisms driving myopic retinopathy. This study provides a mechanistic framework for developing targeted neuroprotective and regeneration-based therapies for pathologic myopia.

Keywords:  axial elongation; microglia; microvascular degeneraton; neurodegeneration; pathologic myopia

DOI:  https://doi.org/10.3389/fncel.2026.1856140