bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2025–02–16
six papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington
  1. Retinal Pigment Epithelium Under Oxidative Stress: Chaperoning Autophagy and Beyond.
  2. Mitochondrial Dysfunction During TGF-β1-Induced Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells.
  3. Oxidative Stress and Energetic Failure: Common Features and Dissimilarities in 3 Different Mouse Models of Retinal Pigment Epithelium Phagocytosis Defects.
  4. Mitochondrial DNA Damage in the Retinal Pigmented Epithelium (RPE) and Its Role in RPE Pathobiology.
  5. Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD).
  6. Cellular Senescence: An Emerging Player in the Pathogenesis of AMD.
  1. Int J Mol Sci. 2025 Jan 30. pii: 1193. [Epub ahead of print]26(3):
    Retinal Pigment Epithelium Under Oxidative Stress: Chaperoning Autophagy and Beyond.
    Yuliya Markitantova, Vladimir Simirskii.
      The structural and functional integrity of the retinal pigment epithelium (RPE) plays a key role in the normal functioning of the visual system. RPE cells are characterized by an efficient system of photoreceptor outer segment phagocytosis, high metabolic activity, and risk of oxidative damage. RPE dysfunction is a common pathological feature in various retinal diseases. Dysregulation of RPE cell proteostasis and redox homeostasis is accompanied by increased reactive oxygen species generation during the impairment of phagocytosis, lysosomal and mitochondrial failure, and an accumulation of waste lipidic and protein aggregates. They are the inducers of RPE dysfunction and can trigger specific pathways of cell death. Autophagy serves as important mechanism in the endogenous defense system, controlling RPE homeostasis and survival under normal conditions and cellular responses under stress conditions through the degradation of intracellular components. Impairment of the autophagy process itself can result in cell death. In this review, we summarize the classical types of oxidative stress-induced autophagy in the RPE with an emphasis on autophagy mediated by molecular chaperones. Heat shock proteins, which represent hubs connecting the life supporting pathways of RPE cells, play a special role in these mechanisms. Regulation of oxidative stress-counteracting autophagy is an essential strategy for protecting the RPE against pathological damage when preventing retinal degenerative disease progression.
    Keywords:  autophagy; chaperone mediated autophagy; heat shock proteins; lysosomes; mitochondrial dysfunction; oxidative stress; phagocytosis; programmed cell death; proteostasis system; retinal pigment epithelium; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3390/ijms26031193
  2. Curr Eye Res. 2025 Feb 12. 1-9
    Mitochondrial Dysfunction During TGF-β1-Induced Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells.
    Xinyi Cheng, Xunyi Gu, Fang Wang.
       PURPOSE: Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells contributes to the epiretinal membrane development in proliferative vitreoretinopathy (PVR). This study aimed at investigating changes in mitochondrial function during EMT in PVR.
    METHODS: Transmission electron microscopy (TEM) was utilized to examine the mitochondrial morphology in human PVR epiretinal membranes and retinal pigment epithelium of human donor eyes. Utilizing TGF-β1 induced EMT in ARPE-19 cells as an in vitro model, we assessed mitochondrial morphology using transmission electron microscopy (TEM), evaluated mitochondrial function through various assays including detection and analysis of mitochondrial membrane potential (MMP), mitochondrial deoxyribonucleic acid (mtDNA), reactive oxygen species (ROS), ATP, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR). RNA sequencing was performed to identify differentially expressed genes (DEGs) related to mitochondrial function and PVR pathogenesis.
    RESULTS: Mitochondrial morphological damage was observed in human PVR epiretinal membranes. TGF-β1 treatment led to morphological changes in mitochondria, increased oxidative stress, mitochondrial membrane depolarization, and reduction in mtDNA, mitochondrial respiration, and ATP production, indicating mitochondrial dysfunction in EMT ARPE-19 cells. Furthermore, RNA sequencing data highlighted the dysfunction, showing downregulation of mitochondria-related pathways and mitochondrial transcription factor A (TFAM), crucial for mtDNA maintenance.
    CONCLUSION: Our findings indicated that TGF-β1 treatment induced mitochondrial dysfunction in RPE cells during EMT, providing insights into the molecular mechanisms of PVR development.
    Keywords:  EMT; PVR; RPE cells; TGF-β1; mitochondria
    DOI:  https://doi.org/10.1080/02713683.2025.2464783
  3. Adv Exp Med Biol. 2025 ;1468 259-263
    Oxidative Stress and Energetic Failure: Common Features and Dissimilarities in 3 Different Mouse Models of Retinal Pigment Epithelium Phagocytosis Defects.
    Elora M Vanoni, Julie Enderlin, Quentin Rieu, Florian Hamieh, Salomé Réty, Emeline F Nandrot.
      Amidst the various crucial functions ensured by retinal pigment epithelial (RPE) cells is the circadian phagocytosis of oxidized photoreceptor outer segments (POS) extremities. We have been exploring three mouse models with defective RPE phagocytosis: β5-/- mice inactivated for the αvβ5 integrin synchronizing phagocytosis, MerTKCR knockin mice devoid of the MerTK internalization receptor cleavage site, and Pre-mRNA Processing Factors 31 knockout mice, PRPF splicing factor mutations constituting the second most important cause of autosomic dominant retinitis pigmentosa in patients. Failure in mitochondrial activity and energetic metabolism has been detected in all three models. Signs of cellular stress and increasing oxidative processes were observed in β5-/- and Prpf31+/- RPE cells, while MerTKCR mutants seem to be sensitive to light-derived stress associated with augmented retinal inflammation. Taken together, these results highlight some common pathological mechanisms in these mice, as well as particular features related to the specific function of each protein.
    Keywords:  Animal models; Beta5 integrin; Energetic metabolism; MerTK; Oxidative stress; Phagocytosis; Prpf splicing factors; Retinal pigment epithelium
    DOI:  https://doi.org/10.1007/978-3-031-76550-6_43
  4. Adv Exp Med Biol. 2025 ;1468 375-379
    Mitochondrial DNA Damage in the Retinal Pigmented Epithelium (RPE) and Its Role in RPE Pathobiology.
    Raela B Ridley, Ashley C Amontree, Alfred S Lewin, Cristhian J Ildefonso.
      Retinal pigmented epithelial (RPE) cells have critical functions in the retina. These cells rely heavily on their mitochondria to generate energy, offer metabolites for biosynthesis through the TCA cycle, regulate apoptosis, and process lipids from photoreceptors. Therefore, mitochondrial damage has significant consequences for the RPE and, by proxy, photoreceptors. Researchers have identified damaged mitochondrial DNA (mtDNA) accumulation in patient samples from aged and diseased individuals. These damages include point mutations and complete deletions of mtDNA segments. The most significant observation in these studies is a positive correlation between the accumulation of damaged mtDNA with the stage of AMD rather than aging. This chapter will discuss how mitochondrial dysfunction in the RPE can drive disease pathobiology by altering their physiological functions.
    Keywords:  Age-related macular degeneration; DNA repair; Mitochondria; Retina pigmented epithelium; Senescence
    DOI:  https://doi.org/10.1007/978-3-031-76550-6_62
  5. Sci Rep. 2025 Feb 10. 15(1): 4256
    Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD).
    Britney N Lizama, Eloise Keeling, Eunah Cho, Evi M Malagise, Nicole Knezovich, Lora Waybright, Emily Watto, Gary Look, Valentina Di Caro, Anthony O Caggiano, J Arjuna Ratnayaka, Mary E Hamby.
      Trafficking defects in retinal pigmented epithelial (RPE) cells contribute to RPE atrophy, a hallmark of geographic atrophy (GA) in dry age-related macular degeneration (AMD). Dry AMD pathogenesis is multifactorial, including amyloid-β (Aβ) accumulation and oxidative stress-common features of Alzheimer's disease (AD). The Sigma-2 receptor (S2R) regulates lipid and protein trafficking, and S2R modulators reverse trafficking deficits in neurodegeneration in vitro models. Given overlapping mechanisms contributing to AD and AMD, S2R modulator effects on RPE function were investigated. The S2R modulator CT1812 is in clinical trials for AD, dementia with Lewy bodies, and GA. Leveraging AD trials testing CT1812, unbiased analyses of patient biofluid proteomes revealed that proteins altered by CT1812 associated with GA and macular degeneration disease ontologies and overlapped with proteins altered in dry AMD. Differential expression analysis of RPE transcripts from APP-Swedish/London mutant transgenic mice, a model featuring Aβ accumulation, revealed reversal of autophagy/trafficking transcripts in S2R modulator-treated animals versus vehicle toward healthy control levels. Photoreceptor outer segment (POS) trafficking in human RPE cells showed deficits in response to Aβ1-42 or hydrogen peroxide compared to vehicle. S2R modulators normalized stressor-induced POS trafficking deficits, resembling healthy control. Taken together, S2R modulation may provide a novel therapeutic strategy for dry AMD.
    DOI:  https://doi.org/10.1038/s41598-025-87921-9
  6. Adv Exp Med Biol. 2025 ;1468 33-37
    Cellular Senescence: An Emerging Player in the Pathogenesis of AMD.
    Vilas Wagh, Nivedita Damodaren, Sharad K Mittal, Fabian L Cardenas-Diaz, Hong Sun, Alexander V Loktev, Vanessa M Peterson, Janmeet S Saini.
      Age-related macular degeneration (AMD) is the leading cause of blindness in the aged population. The accumulation of abnormal extracellular drusen deposits between the retinal pigment epithelium (RPE) and Bruch's membrane is a significant driver of AMD pathology. Drusen deposition leads to the degeneration of RPE cells and, subsequently, photoreceptors, driving the disease to its advanced stages and ultimately resulting in complete vision loss. Although the exact mechanisms underlying the AMD pathogenesis are not fully understood, it is hypothesized that the disease begins with the dysfunction of the RPE, triggering the complement and pro-inflammatory cascade. Over the last decade, new findings have implicated the involvement of cellular senescence (CS) in the pathology of age-related disorders. Specifically for AMD, evidence suggests that the senescence of RPE cells may play a role in the pathogenesis of the disease. In this review, we discuss the potential role of senescence in the onset and progression of AMD and propose potential therapeutic interventions that could be developed by targeting senescence.
    Keywords:  Age-related macular degeneration (AMD); Aging; Cellular senescence; Drusen; Pathogenesis; Retina; Retinal pigment epithelium (RPE); Therapeutics
    DOI:  https://doi.org/10.1007/978-3-031-76550-6_6
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