bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2026–09–27
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa
  1. Targeted Intracellular Metal Modulation Attenuates Oxidative Stress and Preserves Retinal Integrity and Function in a Zebrafish Model of Mitochondrial Dysfunction and Age-Related Retinal Degeneration.
  2. A Microfluidic Gradient Platform for High-Throughput Evaluation of Blue-Light-Induced Oxidative Stress and Antioxidant Protection in Retinal Pigment Epithelial Cells.
  3. Cynarin Alleviates Sodium Iodate-Induced Retinal Pigment Epithelium Injury by Regulating Oxidative Stress and Inflammation.
  4. Toll-like receptor 9 in retinal pigment epithelial cells: Expression, function and the role of TGF-β1.
  5. Assessing mitochondrial phenotypes in a cybrid model of dry age-related macular degeneration.
  6. The MTRNR2L gene family and age-related macular degeneration.
  7. Integrative Proteogenomics and Single-Cell Transcriptomics Prioritize Candidate Causal Proteins and Therapeutic Targets in Age-Related Macular Degeneration.
  1. Int J Mol Sci. 2026 Sep 16. pii: 8265. [Epub ahead of print]27(18):
    Targeted Intracellular Metal Modulation Attenuates Oxidative Stress and Preserves Retinal Integrity and Function in a Zebrafish Model of Mitochondrial Dysfunction and Age-Related Retinal Degeneration.
    Itzchak Angel, Kalaichitra Periyasamy, Micha Gladnikoff, Benin Joseph, Raphael Mayer, Erez Aminov.
      Retinal degeneration is associated with mitochondrial dysfunction, oxidative stress, and disruption of metal homeostasis within the retinal pigment epithelium (RPE). Dysregulation of redox-active metals has been implicated in age-related macular degeneration (AMD), but whether targeted intracellular metal modulation preserves retinal structure and function remains incompletely understood. This study explores the effect of metal ion modulation on retinal structure and visual function. Telomir-Zn, a Zinc-based intracellular metal modulator, depletes labile Fe2+, potently inhibits multiple JmjC KDMs, and induces epigenetic reprogramming. In a zebrafish model combining impaired DNA repair with accelerated mitochondrial oxidative stress and progressive retinal degeneration (Sen57^wrn-/-^ND6^-/+^), Telomir-Zn reduced oxidative stress, preserved retinal architecture, improved visual behaviors, and partially normalized telomeric content and CpG methylation patterns. Complementary studies in human ARPE-19 RPE cells showed attenuation of iron/copper-induced ROS and calcium dysregulation, with reciprocal zinc accumulation and labile Fe2+ depletion. These findings suggest that targeted metal modulation and multi-KDM inhibition may be a novel strategy to mitigate oxidative-epigenetic stress to preserve retinal structure/function in degenerative disease, supporting further investigation and development for AMD.
    Keywords:  JmjC histone demethylases; KDM inhibition; age-related macular degeneration; epigenetic reprogramming; intracellular metal modulation; oxidative stress; retinal degeneration; zebrafish model
    DOI:  https://doi.org/10.3390/ijms27188265
  2. Biosensors (Basel). 2026 Sep 12. pii: 516. [Epub ahead of print]16(9):
    A Microfluidic Gradient Platform for High-Throughput Evaluation of Blue-Light-Induced Oxidative Stress and Antioxidant Protection in Retinal Pigment Epithelial Cells.
    Hon-Man-Herman Tam, Sheng-Yen Wang, Yung-Shin Sun, Kai-Yin Lo.
      The retinal pigment epithelium (RPE) is a monolayer of cells located between retinal photoreceptors and the choroid, playing a critical role in maintaining visual function by protecting the retina and supporting photoreceptor metabolism. Damage to RPE cells can lead to visual disorders, including macular degeneration. Chronic exposure to high-energy blue light has been shown to elevate intracellular reactive oxygen species (ROS) in RPE cells, causing oxidative stress and cellular damage. In this study, a microfluidic platform incorporating a gradient-generating structure was developed to establish controllable and stable gradients of blue light intensity and chemical concentrations. This platform was used to investigate the effects of varying blue light intensities and antioxidant concentrations on oxidative stress in human RPE cells ARPE-19. Cells cultured within the microfluidic channels were exposed to different blue light intensities in combination with chemical treatments. Results demonstrated that ROS production increased with higher blue light intensity, whereas higher antioxidant concentrations effectively reduced ROS accumulation, supporting the ability of these antioxidants to attenuate blue-light-induced intracellular oxidative stress. The present microfluidic device enables simultaneous evaluation of multiple conditions within a single experiment, reducing reagent consumption and enhancing experimental efficiency. This in vitro microfluidic platform integrates chemical and light gradients to assess retinal oxidative damage and antioxidant effects, offering significant potential for ophthalmic drug screening and investigations of retinal protective mechanisms.
    Keywords:  antioxidants; blue light; microfluidics; reactive oxygen species; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/bios16090516
  3. Biomolecules. 2026 Aug 24. pii: 1227. [Epub ahead of print]16(9):
    Cynarin Alleviates Sodium Iodate-Induced Retinal Pigment Epithelium Injury by Regulating Oxidative Stress and Inflammation.
    Yue-Lin Fang, Yu-Jou Hsu, Chao-Hsien Sung, Chia-Chi Kung, Shiuan-Ruei Shiu, Chih-Yu Hung, Mei-Jung Chen, Der-Chen Chang, I-Chia Liang, Chi-Feng Hung.
      Background: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and is strongly driven by oxidative stress and inflammation. This study investigated the protective effects of cynarin against sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) injury, focusing on the MAPK and NF-κB signaling pathways. Materials and Methods: Human ARPE-19 cells were exposed to NaIO3, and cell viability was assessed by the MTT assay. Protein expression of MAPK components (p38, JNK, ERK) and the NF-κB pathway was analyzed by Western blotting, and pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) mRNA expression was measured by RT-qPCR. In vivo, NaIO3-induced retinal degeneration in C57BL/6 mice was treated with cynarin (3 or 10 mg/kg) for seven days, and retinal changes were evaluated by fundus photography, fluorescein angiography, and OCT. Results: Cynarin preserved ARPE-19 cell viability without cytotoxicity. It significantly attenuated NaIO3-induced p38 and JNK phosphorylation, IκB degradation, and NF-κB activation while downregulating IL-1β, IL-6, and TNF-α expression. In vivo, cynarin reduced drusen-like lesions, hyperfluorescent abnormalities, and retinal thinning, and dose-dependently suppressed ocular pro-inflammatory cytokines. Conclusions: Cynarin protects against oxidative stress-induced retinal degeneration by suppressing MAPK and NF-κB inflammatory signaling, representing a promising therapeutic candidate for preventing or delaying NaIO3-induced dry AMD-like retinal injury.
    Keywords:  MAPK; NF-κB; age-related macular degeneration; cynarin; inflammation; oxidative stress; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/biom16091227
  4. Mol Vis. 2026 ;32 210-230
    Toll-like receptor 9 in retinal pigment epithelial cells: Expression, function and the role of TGF-β1.
    Elisabeth Esser, Heidrun Kuhrt, Focke Ziemssen, Margrit Hollborn.
       Purpose: Inflammatory processes in the aged retina may be exacerbated by systemic infection with viruses and bacteria, potentially aggravating age-related macular degeneration (AMD). Toll-like receptors (TLR) are key mediators in detecting pathogen-associated molecular patterns (PAMPs) and host-derived damage-associated molecular patterns (DAMPs). This study aimed to investigate TLR gene expression in cultured retinal pigment epithelial (RPE) cells, focusing particularly on TLR9.
    Methods: TLR gene expression was assessed using semiquantitative qPCR, while protein expression was evaluated through western blotting, immunocytochemistry, and ELISA. Hypoxic conditions were simulated using CoCl2 or by incubation in a 0.1% O2 atmosphere. RPE cell proliferation and viability were examined using bromodeoxyuridine (BrdU) and MTT assays. Cell necrosis and apoptosis were analyzed with a cellular DNA fragmentation ELISA.
    Results: Among the TLRs analyzed, TLR9 showed the most pronounced upregulation under hypoxic conditions. TLR9 protein expression was similarly induced by CoCl2 as well as in a 0.1% O2 atmosphere. Hypoxia increased the protein levels of γH2A.X, a marker for DNA damage and cellular senescence. The TLR9 agonist ODN 1826 induced the gene expression of downstream signaling molecules (MYD88, IRF7, RELA), inflammatory factors (IFNA, COX2), and MMP9 as well as the secretion of TGF-β1. These effects were reversed by TLR9 inhibitors (ODN 2088 and ODN INH-18). Transforming growth factor (TGF)-β1 significantly suppressed the TLR9 expression at both the mRNA and protein levels. This suppressive effect was reversed at the RNA level by inhibiting components of the TGF-β1 signaling pathway, including activin receptor-like kinase (ALK), Smad3, p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and phosphatidylinositol 3-kinase (PI3K) under hypoxic conditions.
    Conclusions: TLR9 activation under hypoxic conditions initiates pro-inflammatory pathways in RPE cells. In the aging retina, viral and bacterial infections and/or DAMPs may further amplify these responses, worsening retinal degeneration. TGF-β1 may exert protective, anti-inflammatory effects by downregulating TLR9 expression.
    DOI:  https://doi.org/10.63500/mv_v32_210
  5. Mol Vis. 2026 ;32 196-208
    Assessing mitochondrial phenotypes in a cybrid model of dry age-related macular degeneration.
    Jacob Dohl, Nyan Lin Zaw, Jett Nguyen, Gordon Burns, Brandon Park, Shari Atilano, Kevin Schneider, Marilyn Chwa, Maria Cristina Kenney.
       Purpose: Dry age-related macular degeneration (DAMD) is the leading cause of vision loss in developed countries, yet there are no FDA-approved treatments currently available. Mitochondria play a significant role in the pathology of DAMD; the retinal pigment epithelium cells of patients with DAMD exhibit mitochondrial dysfunction, elevated levels of mitochondrial DNA lesions, and increased mitochondrial reactive oxygen species. Investigations into the mitochondrial contributions to DAMD are complex as human tissue is challenging to acquire, and animal models do not fully recapitulate disease phenotypes. Cytoplasmic hybrid (cybrid) cells, formed by depleting the mitochondria of an immortalized cell line and fusing with patient platelets, are a possible model for mitochondrial studies on DAMD. This study evaluates if cybrid models of DAMD recapitulate the mitochondrial hallmarks of the disease, including mitochondrial dysfunction, decreased mitochondrial protein levels, lipid accumulation, and mitochondrial DNA lesions.
    Methods: The mitochondrial functions of five healthy and five DAMD cybrid cell lines were compared based on mitochondrial oxygen consumption rates, membrane potential, and protein expression. Secondary factors of mitochondrial dysfunction, including lipid accumulation and mitochondrial DNA stress response, were also examined.
    Results: Compared to healthy control cybrid lines, we found no alterations in bioenergetics, protein levels, and lipid accumulation in DAMD cybrid lines. Mitochondrial DNA stress responses were aberrant in DAMD cybrids compared to healthy controls, suggesting some conserved mitochondrial dysfunction.
    Conclusions: Taken together, this study suggests that these DAMD cybrids do not fully recapitulate DAMD mitochondrial pathology, though this is limited to the study population of males with the H mtDNA haplogroup. However, there may be a niche for cybrid cell lines in investigating mitochondrial DNA phenotypes in patients with DAMD. This is likely because DAMD is a multifactorial disease, dependent upon an individual's genetics and the retinal microenvironment.
    DOI:  https://doi.org/10.63500/mv_v32_196
  6. Front Immunol. 2026 ;17 1925795
    The MTRNR2L gene family and age-related macular degeneration.
    Adam Moosa, Joshua J Wang, Margaret M DeAngelis, Sarah X Zhang.
      Age-related macular degeneration (AMD) is the leading cause of blindness in aging adults, yet no FDA-approved therapies exist for early and intermediate disease. Multiple interconnected pathways, including mitochondrial dysfunction, oxidative stress, and inflammation, contribute to retinal pigment epithelium (RPE) degeneration in AMD, highlighting the need for developing new cytoprotective strategies. The MTRNR2L gene family, comprising nuclear paralogs of mitochondrial-derived peptide humanin, has emerged as a potential regulator of these pathways. Humanin has demonstrated anti-apoptotic, anti-inflammatory, and mitochondrial-stabilizing effects across multiple cell types, including the RPE. Recent transcriptomic and single-cell RNA-sequencing (scRNA-seq) analyses indicate that MTRNR2L genes are upregulated in a variety of human diseases associated with cellular stress response, inflammation, angiogenesis, and neurodegeneration. These findings suggest that MTRNR2L genes participate in coordinated stress-adaptive programs and may mirror humanin's cytoprotective and immunomodulating actions. This review summarizes recent research advances and highlights key gaps for understanding the roles of the MTRNR2L family in RPE protection and AMD progression.
    Keywords:  AMD (age-related macular degeneration); MTRNR2L; cytoprotection; humanin; mitochondrial derived peptides; oxidative stress; retina pigment epithelial cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1925795
  7. Int J Mol Sci. 2026 Sep 11. pii: 8103. [Epub ahead of print]27(18):
    Integrative Proteogenomics and Single-Cell Transcriptomics Prioritize Candidate Causal Proteins and Therapeutic Targets in Age-Related Macular Degeneration.
    Lei Wen, Fangran Li, Yuan Liu, Ka Zhang, Aiqin Mao, Liangju Liu, Xiaowang Lv, Li Geng, Fan Yu, Lei Feng, Hao Kan.
      Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment, yet identifying effector proteins and tissue-specific mechanisms underlying genome-wide association study (GWAS) loci remains challenging. This study aimed to systematically prioritize candidate causal circulating proteins and delineate their cellular and transcriptional dynamics in AMD. We integrated plasma protein quantitative trait loci (pQTL) summary statistics from the UK Biobank Pharma Proteomics Project (UKB-PPP; N=53,022) with FinnGen AMD GWAS data using proteome-wide association studies (PWAS), summary-data-based Mendelian randomization (SMR) with the HEIDI test, and Bayesian colocalization analysis. Prioritized candidates were mapped across human and murine retinal single-cell/single-nucleus RNA sequencing atlases. Transcriptional responsiveness was validated in an independent clinical microarray dataset (GSE103060) and in human retinal pigment epithelial cells (ARPE-19) via in vitro inflammatory stimulation and RT-qPCR. Target tractability was assessed using pharmacological databases. Multi-stage genetic screening prioritized five candidate proteins stratified into two confidence tiers: three Tier 1 causal drivers supported by colocalization (PP4 > 0.80)-including risk factors CSF2, IL20RB, and WARS1 (also known as WARS)-alongside two Tier 2 candidates supported by SMR and HEIDI, comprising risk factor PILRA and inversely associated metabolic factor ACADSB. Retinal transcriptomic mapping localized PILRA specifically to microglia, ACADSB to inner retinal neurons, and WARS1 to photoreceptors, RPE, and vascular compartments, while IL20RB and CSF2 exhibited low baseline expression. In independent validation cohorts, IL20RB and WARS1 were significantly up-regulated in choroidal neovascularization (CNV) membrane-derived RPE from patients with AMD (p<0.01). Exposure of ARPE-19 cells to TNF-α markedly induced mRNA levels of IL20RB (P=0.0025) and WARS1 (p<0.0001). Dual normalization against ACTB as a secondary internal reference yielded consistent significant induction. Pathway enrichment highlighted cytokine-driven receptor cascades (JAK-STAT signaling) and mitochondrial substrate catabolism (branched-chain amino acid and fatty acid metabolism). Drug-target profiling identified small molecules and nutraceuticals interacting with ACADSB, CSF2, and WARS1. By combining large-scale plasma proteomic genetics with single-cell mapping and experimental validation, this study identifies a prioritized set of candidate causal proteins linking neuroimmune activation, vascular remodeling, and mitochondrial bioenergetics in AMD, providing candidate entry points for mechanistic and therapeutic exploration.
    Keywords:  age-related macular degeneration; protein quantitative trait loci; proteome-wide association studies; single-nucleus RNA sequencing; summary-data-based mendelian randomization
    DOI:  https://doi.org/10.3390/ijms27188103
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