bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2026–07–05
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa
  1. A Critical Role for Mitochondrial Dynamics in Cigarette Smoke Condensate-induced RPE Senescence.
  2. Mitochondrial Dysfunction and Diabetic Retinopathy: Research Progress from Pathogenic Mechanisms to Therapeutic Targets.
  3. Freeze-Dried Extracts of Eruca sativa Selectively Inhibit Nuclear Factor-κB and Vascular Endothelial Growth Factor Levels in Retinal Pigment Epithelial Cells.
  4. [Light stress-induced damage to intracellular membrane organelles and its preventive strategies].
  5. Molecular mechanisms and intervention strategies for age-related macular degeneration.
  6. NAD+ modulates mitochondrial vulnerability in MERTK-associated models of retinitis pigmentosa.
  7. ApoE- and Cfh-deficient mice exhibit structural and molecular features of human early-intermediate retinal degeneration.
  1. Free Radic Biol Med. 2026 Jul 01. pii: S0891-5849(26)00915-9. [Epub ahead of print]
    A Critical Role for Mitochondrial Dynamics in Cigarette Smoke Condensate-induced RPE Senescence.
    Qi Zhou, Zunyi Zhang, Yinga Wu, Chunmin Dong, Chen-Chuan Wu, James T Handa, Jing Ma, Shusheng Wang.
      Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Its pathogenesis remains incompletely understood, partly due to the complex interplay of genetic risk, aging, and environmental stressors. Cigarette smoking (CS) is a major modifiable risk factor for AMD, yet the mechanism linking CS to disease progression remains unclear. We hypothesize that CS accelerates AMD pathogenesis by exacerbating cellular senescence in the retinal pigment epithelium (RPE), thereby driving age-related RPE dysfunction and degeneration. In this study, differentiated ARPE-19 cells or mice were exposed to low-dose cigarette smoke condensate (CSC), and stress-induced senescence-like RPE phenotypes were induced, characterized by increased senescence markers, mitochondrial dysfunction, and retinal functional impairment. RPE senescence phenotypes were also confirmed in mice exposed to 6 months of CS in the smoking chamber. CSC-induced RPE senescence was associated with a biphasic alteration in mitochondrial morphology, progressing from early mitochondrial fragmentation to late mitochondrial hyperfusion, as well as impaired mitophagy flux, reduced mitochondrial turnover, and decreased mitochondrial biogenesis. Mechanistically, CSC increased dynamin-related protein 1 (DRP1) phosphorylation and promoted cleavage of the mitochondrial phosphatase PGAM5, mitochondrial remodeling associated with decreased DRP1 activities, elevated mitochondrial oxidative stress, and activation of mTOR signaling. Notably, overexpression of a DRP1 activity mutant (K38A) mimics the CSC-induced RPE senescence, while overexpression of the phosphodeficient DRP1-S637A mutant significantly attenuates both mTOR signaling and CSC-induced RPE senescence by restoring mitochondrial fission balance, improving mitochondrial quality-control responses, reducing mitochondrial oxidative stress. Collectively, these findings identify impaired DRP1-dependent mitochondrial remodeling as a key mechanism linking CSC exposure to RPE senescence. While we confirmed the RPE senescence phenotype in mice after 6 months of CS exposure, the specific mechanisms observed in this study require further validation in a chronic CS model. These findings encourage future research into mitochondrial dynamics and RPE senescence in AMD, suggesting that modulating RPE mitochondrial dynamics holds therapeutic potential for delaying AMD progression.
    Keywords:  Age-related macular degeneration; Cellular senescence; Cigarette smoke; DRP1; Mitochondrial ROS; Mitochondrial dynamics; Mitophagy; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.060
  2. Exp Eye Res. 2026 Jul 03. pii: S0014-4835(26)00313-1. [Epub ahead of print] 111157
    Mitochondrial Dysfunction and Diabetic Retinopathy: Research Progress from Pathogenic Mechanisms to Therapeutic Targets.
    Xiaoyan Zhu, Tao Jin, Yu Zhang, Lulu Lian, Wanli Du.
      Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus (DM) and remains a major cause of visual impairment and blindness in adults. Accumulating evidence indicates that DR is not merely a microvascular disorder, but a complex neurovascular disease driven by long-standing hyperglycemia, metabolic dysregulation, oxidative stress, chronic inflammation, neurodegeneration, and impaired neurovascular coupling. Mitochondria are central regulators of cellular energy metabolism and redox homeostasis, and mitochondrial dysfunction is increasingly recognized as a pivotal mechanism linking hyperglycemia-induced metabolic abnormalities to retinal neurovascular unit injury. Under persistent hyperglycemic conditions, excessive glucose flux and metabolic overload promote mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impaired oxidative phosphorylation, mitochondrial fusion-fission imbalance, defective mitochondrial biogenesis, dysregulated mitophagy, metabolic reprogramming, and epigenetic alterations. These abnormalities lead to ATP depletion, inflammatory amplification, and activation of multiple forms of programmed cell death, including apoptosis, ferroptosis, pyroptosis, necroptosis, and poly(ADP-ribose) polymerase 1 (PARP1)-dependent cell death. Mitochondrial injury affects retinal endothelial cells, pericytes, Muller cells, microglia, retinal ganglion cells, photoreceptors, and retinal pigment epithelial cells in a cell-type-specific manner, ultimately contributing to blood-retinal barrier disruption, capillary occlusion, neurovascular coupling impairment, retinal neurodegeneration, and progression from non-proliferative to proliferative DR. This review summarizes recent advances in mitochondrial dysfunction in DR, focusing on oxidative stress, mtDNA injury, mitochondrial metabolic reprogramming, mitochondrial dynamics, mitochondrial biogenesis, mitophagy, epigenetic regulation, mitochondria-associated cell death, and neurovascular unit dysfunction. Emerging mitochondria-targeted therapeutic strategies, including mitochondrial antioxidants, modulation of mitochondrial biogenesis and dynamics, mitophagy regulation, mtDNA protection, ferroptosis and inflammasome inhibition, epigenetic intervention, are also discussed. A deeper understanding of mitochondrial mechanisms may provide new therapeutic targets and translational opportunities for DR prevention and treatment.
    Keywords:  diabetic retinopathy; epigenetic modification; mitochondrial DNA; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neurovascular unit; oxidative stress; therapeutic targets
    DOI:  https://doi.org/10.1016/j.exer.2026.111157
  3. Prev Nutr Food Sci. 2026 ;pii: pnf.2026.004. [Epub ahead of print]31(3):
    Freeze-Dried Extracts of Eruca sativa Selectively Inhibit Nuclear Factor-κB and Vascular Endothelial Growth Factor Levels in Retinal Pigment Epithelial Cells.
    Minseo Cho, Jisu Lee, Jiwoo Lee, Caglar Doguer, Jeong Ho Hwang, Jung-Heun Ha.
      Diabetic retinopathy and age-related macular degeneration are driven by retinal pigment epithelium (RPE) dysfunction accompanied by chronic inflammation and an upregulation of vascular endothelial growth factor (VEGF). This study investigated the protective effects of Eruca sativa freeze-dried extract against metabolic and inflammatory stress in the ARPE-19 retinal epithelial cell line. Gene expression levels and protein contents were assessed via quantitative real-time polymerase chain reaction and Western blots. VEGF secretion and cell calcium levels were quantified using enzyme-linked immunosorbent assay and Fluo-4 NW calcium assay, respectively. Freeze-dried E. sativa extract (ESF) exposure did not induce any cytotoxicity across the concentration range tested. Under thapsigargin (Tg) stimulation, ESF at 1 mg/mL significantly reduced VEGF expression and protein secretion by 32% and 34%, respectively. Tg-induced calcium mobilization within cells and the expression of unfolded protein response markers, including CCAAT/enhancer-binding protein homologous protein, binding immunoglobulin protein, and X-box binding protein-1, remained unchanged following ESF exposure. Under lipopolysaccharide stimulation, in a dose-dependent manner, ESF suppressed nuclear factor-κB (NF-κB) phosphorylation, tumor necrosis factor-α, and interleukin-1β expression; however, c-Jun N-terminal kinase signaling was not affected. Hot-air-dried E. sativa extract demonstrated contrasting regulatory profiles, which exhibited a broader modulation of endoplasmic reticulum stress and mitogen-activated protein kinase signaling. Collectively, the findings demonstrate that ESF selectively attenuates inflammatory and angiogenic responses by specifically inhibiting the NF-κB-VEGF axis. Dehydration, therefore, is a critical method determining ESF bioactivity, preserving native phytochemicals that confer focused anti-inflammatory and anti-angiogenic efficacy in RPE cells.
    Keywords:  Eruca sativa; NF-kappa B; inflammation; retinal pigment epithelium; vascular endothelial growth factors
    DOI:  https://doi.org/10.3746/pnf.2026.004
  4. Nihon Yakurigaku Zasshi. 2026 ;161(4): 257-262
    [Light stress-induced damage to intracellular membrane organelles and its preventive strategies].
    Wataru Otsu.
      Photoreceptor cells in the retina are highly specialized sensory cells that function as light receptors. During the conversion of light into neural signals, photoreceptors are constantly exposed to oxidative stress. Although environmental stressors, such as excessive light exposure, have been implicated in the progression of various retinal diseases, including dry age-related macular degeneration (AMD), the molecular mechanisms underlying the light-induced stress response remain incompletely elucidated. Excessive light exposure triggers the endoplasmic reticulum (ER) stress response in cells and also induces mitochondrial dysfunction characterized by depolarization and fragmentation, ultimately leading to cell death. We have shown that compounds derived from natural products, such as delphinidins and pentadecyl, exert protective effects against blue light-induced cellular damage. Furthermore, crocetin, a natural carotenoid pigment, has been shown to suppress ultraviolet-A (UV-A)-induced mitochondrial fragmentation in corneal epithelial cells. In this review, we provide an overview of light stress-induced injuries to intracellular membrane organelles, particularly mitochondria and the ER, and the cellular response mechanisms that are mediated through these organelles. These findings suggest that maintaining the homeostasis of intracellular membrane organelles represents an important therapeutic target for the prevention and treatment of retinal degenerative diseases.
    DOI:  https://doi.org/10.1254/fpj.26030
  5. Int J Ophthalmol. 2026 ;19(7): 1383-1394
    Molecular mechanisms and intervention strategies for age-related macular degeneration.
    Ru-Yuan Zhang, Hui-Min Su, Yi Ding, Yuan-Yuan Zou.
      Age-related macular degeneration (AMD) is a leading ocular disorder that causes irreversible visual impairment and blindness in the elderly population. Accumulating evidence demonstrates that AMD is the end-stage outcome of various retinal degenerative lesions and vascular anomalies. Its core pathogenic mechanisms mainly involve dysfunction and atrophy of retinal pigment epithelium (RPE) cells, choroidal capillary degeneration, pathological choroidal neovascularization (CNV), chronic inflammation, oxidative stress injury, deposition of extracellular substances such as drusen, and genetic predisposition. Given its multifactorial origin and complicated pathophysiological processes, the full molecular regulatory network of AMD has not been fully clarified, which restricts the development of more efficient intervention regimens. This review systematically summarizes the latest research progress concerning the molecular mechanisms of AMD, and comprehensively discusses mainstream and emerging therapeutic strategies, including anti-vascular endothelial growth factor (VEGF) drugs, antioxidant and mineral supplements, photodynamic therapy, and laser therapy, as well as innovative modalities such as gene therapy, stem cell therapy, and targeted regulation of complement and inflammatory pathways. It is intended to provide theoretical basis and research references for in-depth mechanistic exploration, early prevention and precise clinical management of AMD.
    Keywords:  age-related macular degeneration; intervention therapy; molecular mechanism; retinal pigment epithelium
    DOI:  https://doi.org/10.18240/ijo.2026.07.20
  6. Nat Commun. 2026 Jun 27.
    NAD+ modulates mitochondrial vulnerability in MERTK-associated models of retinitis pigmentosa.
    Lujia Feng, Yuwen Wen, Ting Zhang, Xiaohua Zhuo, Yantao Wei, Lixian Liu, Zhaohao Huang, Guoming Zhang, Lu Chen, Yong Du, Dong Fang, Wangting Li, Linbin Zhou, Ling Zhao, Yingting Zhu, Jia Liang, Zhiquan Li, Xiaojing Song, Caibin Deng, Xingxing Mao, Xiaofeng Hou, Wenru Su, Wei Chi, Yehong Zhuo, Shaochong Zhang.
      Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease leading to blindness. RP is characterized by progressive loss of photoreceptors and retinal pigment epithelium (RPE), leading to retinal degeneration. The mechanisms that initiate RP and drive retinal vulnerability are poorly understood, and new strategies for preventing and treating RP are urgently needed. Although mitochondrial dysfunction initiates many neurodegenerative diseases, the contribution of mitochondrial dysfunction to RP is unclear. Single-cell RNA sequencing, transmission electron microscopy, and enzyme-linked immunosorbent assays revealed that photoreceptor and RPE cells have abnormal mitochondria in rats with RP. Nicotinamide adenine dinucleotide (NAD+) metabolism decreased in rats with RP, increasing the vulnerability to disease-related insults. Similar experimental results were observed in a Mer tyrosine kinase receptor (MERTK)-associated RP primary human RPE cell model. Electroretinography, immunofluorescence, and fundus photography revealed that oral administration of the NAD+ precursor nicotinamide mononucleotide (NMN) protected rats with RP from retinal degeneration. Single-cell RNA sequencing, siRNA targeting, and Adeno-associated virus applications demonstrated that NMN elicits therapeutic effects via the glyceraldehyde-phosphate dehydrogenase-mitochondria pathway. These results indicate that mitochondrial abnormalities may be drivers of RP, and NMN elicits therapeutic effects on RP.
    DOI:  https://doi.org/10.1038/s41467-026-74400-6
  7. Animal Model Exp Med. 2026 Jul 01.
    ApoE- and Cfh-deficient mice exhibit structural and molecular features of human early-intermediate retinal degeneration.
    Sergio Recalde, Maite Moreno Orduña, Jaione Bezunartea, Idoia Belza, Ainara Chas, Laura Fernández-Sánchez, Nicolás Cuenca Navarro, Alfredo García-Layana, Patricia Fernández-Robredo, María Hernández.
       BACKGROUND: Age-related macular degeneration (AMD) is a multifactorial retinal disease in which alterations in lipid metabolism and dysregulation of the complement system play a central role. The aim of this study was to characterize a novel double-knockout (DK) mouse model deficient in apolipoprotein E and complement factor H (ApoE-/-Cfh-/-) as an experimental model of early and intermediate AMD.
    METHODS: ApoE-/-Cfh-/- mice and wild-type controls underwent comprehensive morphological, ultrastructural, biochemical, and molecular analyses. Retinal and retinal pigment epithelium (RPE) integrity, Bruch's membrane (BM) morphology, lipid accumulation, complement activation, angiogenic signaling, and synaptic organization were evaluated using histology, electron microscopy, immunohistochemistry, biochemical assays, and gene expression analyses.
    RESULTS: DK mice exhibited significant RPE thinning, disruption of tight junctions, vacuolization, and BM thickening (p < 0.05). Lipid accumulation and plasma lipid levels significantly increased compared with controls (p < 0.01). Complement activation was significantly enhanced, as evidenced by increased C5b-9 deposition (p < 0.01). In addition, DK mice exhibited increased vascular endothelial growth factor expression (p < 0.05), altered matrix metalloproteinase activity (p < 0.05), and significant synaptic disorganization between photoreceptors and second-order neurons (p < 0.05).
    CONCLUSIONS: The ApoE-/-Cfh-/- mouse reproduces key molecular and structural features of early and intermediate retinal degeneration with statistically significant alterations. Although it does not progress to advanced disease stages, it represents a valuable model to investigate several factors of AMD pathogenesis and evaluate therapeutic strategies targeting early disease mechanisms.
    Keywords:  Bruch's membrane; aged macular degeneration; animal model; apolipoprotein E; complement factor H; inflammation; lipid metabolism; retinal pigment epithelium
    DOI:  https://doi.org/10.1002/ame2.70243
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