bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2025–07–06
four papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington



  1. J Neuroinflammation. 2025 Jul 03. 22(1): 173
      Age-related macular degeneration (AMD), a multifactorial type of retinal degeneration represents the most common cause for blindness in elderly. Polymorphisms in complement factor-H increase, while absence of factor-H-related protein-1 (FHR1) decreases the AMD risk, currently explained by their opposing relationship. Here we identify a FHR1-driven pathway fostering chronic cellular inflammation. FHR1 accumulates below the retinal pigment epithelium (RPE) in AMD donor tissue and similarly the murine homolog, muFHR1 is abundant in three AMD-relevant mouse models. These mouse models express the muFHR1 receptor EGF-like module-containing mucin-like hormone receptor 1 (Emr1) on the RPE and on invading mononuclear phagocytes (MP), where both cells form clusters via muFHR1/Emr1. FHR1 ignited EMR2-dependent Ca2+-signals and gene expression in both human RPE cell line and in vivo where muFHR1 affects Emr1+ cells (RPE and MP) gene expression shown by RNAseq analysis. As muFHR1 deletion in mice revealed significantly reduced MP invasion and neoangiogenesis in laser-induced choroidal neovascularization, we hypothesize that FHR1 accumulates, stabilizes and activates MP in the stage of RPE degeneration.
    Keywords:  Age-related macular degeneration; Complement system; Inflammation; Retinal pigment epithelium
    DOI:  https://doi.org/10.1186/s12974-025-03499-z
  2. Aging Dis. 2025 Jun 25.
      In the mammalian retina, photoreceptors rely on the continuous renewal of their outer segments to preserve their function as light-sensing cells, thereby ensuring lifelong vision. This process entails the routine phagocytosis of shed photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE). Phagocytosis of POS by RPE is a highly circadian-regulated process that is dependent on intricate and tightly controlled cellular signaling pathways. This article provides a systematic review of the research on the regulation and functional implications of the RPE phagocytic signaling system. Therefore, a deeper understanding of the role of retinal pigment epithelial phagocytosis in the pathogenesis of retinal degeneration can inform the development of potential therapeutic targets to prevent the irreversible loss of retinal pigment epithelium and photoreceptor cells, thereby preventing retinal degenerative diseases. This article summarizes the soluble and membrane-bound molecules produced by the RPE that are associated with phagocytosis and discusses their specific roles in POS phagocytosis and retinal degenerative disorders, potentially aiding in the prevention or treatment of retinal degenerative diseases.
    DOI:  https://doi.org/10.14336/AD.2025.0542
  3. In Vitro Cell Dev Biol Anim. 2025 Jun 30.
      Nonexudative age-related macular degeneration (dry AMD) is characterized by the progressive degeneration of retinal pigment epithelial (RPE) cells and photoreceptors, resulting in central vision loss. The disease is primarily marked by the accumulation of drusen and RPE atrophy. Given the emerging role of miR-21-5p in various ocular diseases, including diabetic retinopathy, glaucoma, pterygium, and choroidal neovascularization, we hypothesized that miR-21-5p may also impact RPE cell integrity in AMD. To test this hypothesis, we employed a rat model of dry AMD induced by sodium iodate (NaIO3) and evaluated the effects of miR-21-5p modulation via intravitreal injections of miR-21-5p agomir or antagomir. Comprehensive assessments were performed using optical coherence tomography (OCT), fundus imaging, histopathology, and biochemical markers. Our results demonstrated an upregulation of miR-21-5p in response to NaIO3 treatment. Administration of miR-21-5p agomir exacerbated RPE damage, while pretreatment with miR-21-5p antagomir mitigated these detrimental effects. Furthermore, in vitro experiments revealed that miR-21-5p regulates necroptosis in CoCl2-treated RPE cells by targeting Pellino1 (Peli1) via its 3' untranslated region, thereby inhibiting Peli1 expression. Overexpression of Peli1 effectively counteracted the necroptotic effects induced by CoCl2. These findings highlight the potential of miR-21-5p as a therapeutic target in dry AMD, expanding our understanding of miRNA-mediated regulation of RPE cells and suggesting new avenues for treatment strategies.
    Keywords:  AMD; MicroRNA; Necroptosis; RPE
    DOI:  https://doi.org/10.1007/s11626-025-01064-9
  4. Diagn Pathol. 2025 Jul 02. 20(1): 79
       BACKGROUND: Glaucoma is a major eye disease that causes blindness. The loss of retinal ganglion cells (RGCs) due to mitophagy impairment is a key driver of glaucoma. SHMT2 depletion leads to an increase in reactive oxygen species (ROS), but its role in regulating mitophagy remains unclear. This study aims to investigate the mechanism by which SHMT2 contributes to glaucoma through the regulation of RGC mitophagy.
    METHODS: The role of SHMT2 in glaucoma was evaluated through hematoxylin and eosin (H&E) staining and immunofluorescence (IF) staining of acute ocular hypertension (AOH) mouse eyeballs. Mitophagy was assessed by measuring LDH release, apoptosis, mitochondrial membrane potential, lipid ROS, and the protein levels of mitophagy-related proteins in RGCs. The underlying mechanism was investigated using co-immunoprecipitation, IF staining, and Western blot analysis.
    RESULTS: Results showed that SHMT2 expression was decreased in the AOH mouse model. NMDA inhibited mitophagy in RGCs, which was restored by SHMT2 overexpression. Moreover, SHMT2 overexpression stabilized PINK1 expression by enhancing the phosphorylation of PINK1. In vivo experiments suggested that SHMT2 overexpression increased the thickness of the retinal ganglion cell-inner plexiform layer.
    CONCLUSION: This study confirmed that SHMT2 overexpression alleviated glaucoma by enhancing mitophagy in RGCs through the upregulation of PINK1 phosphorylation, suggesting that SHMT2 may serve as a potential therapeutic target for glaucoma.
    Keywords:  Glaucoma; Mitophagy; PINK1; Retinal ganglion cells; SHMT2
    DOI:  https://doi.org/10.1186/s13000-025-01675-6