bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2025–09–28
eight papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington
  1. Transmembrane Protein 97 (TMEM97): Molecular Target and Treatment in Age-Related Macular Degeneration (AMD).
  2. Loss of PIKfyve in Rod Photoreceptors and RPE Cells Leads to Endolysosomal Dysfunction and Retinal Degeneration.
  3. NaIO3-induced RPE toxicity leads to chorioretinal atrophy, scleral remodeling, and myopic axial elongation in mice.
  4. Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models.
  5. Optogenetics: A Novel Therapeutic Avenue for Age-Related Macular Degeneration.
  6. Glaucoma-associated polymorphism M98K-OPTN sensitizes retinal cells to protein homeostasis stress through p62-mediated caspase activation.
  7. The alternative complement pathway drives neuroinflammation and neurodegeneration in mouse models of glaucoma and optic nerve injury.
  8. Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
  1. Biomolecules. 2025 Aug 26. pii: 1228. [Epub ahead of print]15(9):
    Transmembrane Protein 97 (TMEM97): Molecular Target and Treatment in Age-Related Macular Degeneration (AMD).
    Alyssa Stathopoulos, Joshua J Wang, Stephen F Martin, Sarah X Zhang.
      Age-related macular degeneration (AMD) is a common eye disease that significantly affects daily activities and impedes the quality of life in aging adults, yet effective treatments to halt or reverse disease progression are currently lacking. Ongoing research aims at understanding the complex mechanisms underlying AMD pathophysiology involving retinal pigment epithelium (RPE) dysfunction, drusen formation, inflammation, neovascularization, and RPE/photoreceptor degeneration. Sigma 2 receptor/transmembrane protein 97 (σ2R/TMEM97) is a multifunctional protein implicated in cellular processes including cholesterol homeostasis, lysosome-dependent autophagy, calcium homeostasis, and integrated stress response (ISR). Recent genome-wide association studies (GWASs) have identified σ2R/TMEM97 as a novel genetic risk factor strongly associated with AMD development. In this review, we summarize recent research progress on σ2R/TMEM97 in age-related neurodegenerative diseases, highlighting its implication as a molecular target in AMD via regulating oxidative stress, inflammation, lipid uptake, drusen formation, and epithelial-mesenchymal transition (EMT). We also discuss the potential of modulating σ2R/TMEM97 function with novel small-molecule drugs as a promising treatment for dry AMD and the unresolved questions in understanding the mechanistic basis of their actions.
    Keywords:  molecular target and treatment; retinal degeneration; small molecule; transmembrane protein 97
    DOI:  https://doi.org/10.3390/biom15091228
  2. bioRxiv. 2025 Sep 17. pii: 2025.09.15.676371. [Epub ahead of print]
    Loss of PIKfyve in Rod Photoreceptors and RPE Cells Leads to Endolysosomal Dysfunction and Retinal Degeneration.
    Ammaji Rajala, Larissa J Trevino, Thamaraiselvi Saravanan, Tyler M Black, Akbar M Bhat, Tuan Ngo, Mark Eminhizer, Jianhai Du, Visvanathan Ramamurthy, Raju V S Rajala.
      Photoreceptor outer segment (OS) degradation is primarily mediated by retinal pigment epithelial (RPE) cells through daily phagocytosis of shed distal OS tips. In contrast, much less is understood about the cell-autonomous mechanisms photoreceptors use to clear mislocalized molecules caused by protein misfolding or trafficking defects. Mislocalized or excess rhodopsin that fails to reach the OS is retained in the inner segment or cell body, where it is presumably degraded via the endolysosomal system. We identify PIKfyve, a phosphoinositide kinase that generates PI(3,5)P₂, as a key regulator of this pathway. Using Translating Ribosome Affinity Purification (TRAP), we find that PIKfyve is highly expressed in rod photoreceptors. Rod-specific PIKfyve deletion causes progressive retinal degeneration, marked by inner segment vacuolation, elevated LAMP1/2, thinning of the outer nuclear layer, and eventual loss of rod and cone function. Loss of one copy of PIKfyve in rod photoreceptors accelerates degeneration in P23H rhodopsin mutant mice. In RPE cells, PIKfyve loss disrupts phagocytosis and autophagy, leading to accumulation of rhodopsin, LAMP1, LC3A/B, and lipid droplets, along with metabolic disturbances. These findings demonstrate that PIKfyve is essential for photoreceptor and RPE health by regulating lysosomal function, phagocytosis, autophagy and metabolism, and suggest that enhancing PIKfyve activity could be a therapeutic strategy for retinal degenerative diseases.
    DOI:  https://doi.org/10.1101/2025.09.15.676371
  3. Exp Eye Res. 2025 Sep 24. pii: S0014-4835(25)00437-3. [Epub ahead of print] 110665
    NaIO3-induced RPE toxicity leads to chorioretinal atrophy, scleral remodeling, and myopic axial elongation in mice.
    Takafumi Suzuki, Masako Nagahara, Kentaro Hayashi, Tomoyasu Shiraya, Ryo Terao, Megumi Honjo, Takashi Ueta.
      Pathologic myopia, a vision-threatening subtype of myopia, is characterized by axial elongation accompanied by chorioretinal atrophy and scleral remodeling. While lens-induced and form-deprivation myopia models have elucidated the role of visual input in ocular growth, the contribution of retinal pigment epithelium (RPE) and choriocapillaris (CC) damages remains incompletely understood. Here, we employed a sodium iodate (NaIO3) model-traditionally used in age-related macular degeneration research-to investigate whether the damage to the RPE and CC can induce changes in the sclera and axial length. We demonstrate that systemic NaIO3 exposure induced widespread RPE and CC degeneration, retinal thinning, and chorioretinal atrophy, all of which were partially rescued by the ferroptosis inhibitor ferrostatin-1 (Fer-1) in mice. These degenerative changes correlated with a significant myopic shift (∼15 D) and axial elongation (∼0.3 mm), alongside scleral thinning, decreased COL1A1 expression, and reduced collagen fibril diameter-hallmarks of scleral extracellular matrix remodeling. Fer-1 treatment attenuated both the anatomical and molecular features of myopia, supporting a causal role of lipid peroxidation in this process. Our findings demonstrate that lipid peroxidation-associated RPE and CC damage can trigger scleral remodeling and axial elongation independent of visual input, providing a novel mechanistic insight into ocular growth regulation. The NaIO3 model may therefore serve as a unique and reproducible platform for studying chorioretinal degeneration-driven myopia and evaluating lipid peroxidation-targeting therapies.
    Keywords:  Choriocapillaris; Lipid peroxidation; Myopia; RPE; Scleral remodeling; Sodium iodate
    DOI:  https://doi.org/10.1016/j.exer.2025.110665
  4. Sci Rep. 2025 Sep 26. 15(1): 33070
    Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models.
    Allyssa Bradley, Soyoung Park, Soyeon Park, Kyle Kim, Angela Galdamez, Hyejung Min, Monica Sophia Diaz-Aguilar, M Elizabeth Hartnett, Eun-Jin Lee, Jonathan H Lin.
      Pathological retinal neovascularization is a cause of vision loss in diseases including retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and diabetic retinopathy. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism that is activated by ER stress and upregulates many proteins, including angiogenesis factors like VEGF and HIF-1α. This suggests that UPR genes and pathways may drive retinal angiogenesis. Here, we tested the role of the UPR regulator Activating Transcription Factor 6 (ATF6) in pathological and developmental retinal angiogenesis. We induced pathological retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model and found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR transcriptional program induction. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppressed retinal expression of UPR genes. Additionally, in postnatal day 7 Atf6-/- mice when the retinal vasculature is developing in response to physiologic intraocular hypoxia, there was a transient but significant defect in pruning and retinal blood vessel extension. Together, our results demonstrate ATF6's causal role in developmental and pathological retinal angiogenesis and highlight its potential as a therapeutic target to preserve vision in retinal neovascularization diseases.
    DOI:  https://doi.org/10.1038/s41598-025-15393-y
  5. Biomolecules. 2025 Sep 05. pii: 1286. [Epub ahead of print]15(9):
    Optogenetics: A Novel Therapeutic Avenue for Age-Related Macular Degeneration.
    Pier Luigi Grenga, Chiara Ciancimino, Alessandro Meduri, Serena Fragiotta.
      Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, characterized by progressive degeneration of the retinal pigment epithelium (RPE) and photoreceptors in the macula. Current treatment options primarily focus on slowing disease progression in neovascular AMD, while effective therapies for dry AMD remain limited. Optogenetics, a revolutionary technique utilizing light-sensitive proteins (opsins) to control the activity of genetically targeted cells, has emerged as a promising therapeutic strategy for restoring vision in retinal degenerative diseases. In retinal disease models, adeno-associated viruses (AAVs) serve as delivery vectors via intravitreal or subretinal injections. This review explores the principles of optogenetics, its application in preclinical AMD models, and the potential for clinical translation of this approach. We discuss the various optogenetic tools, delivery methods, and the challenges and future directions in harnessing this technology to combat AMD-related vision loss.
    Keywords:  adeno-associated viruses (AAVs); age-related macular degeneration; optogenetics; treatment
    DOI:  https://doi.org/10.3390/biom15091286
  6. Biochim Biophys Acta Mol Cell Res. 2025 Sep 24. pii: S0167-4889(25)00169-7. [Epub ahead of print] 120064
    Glaucoma-associated polymorphism M98K-OPTN sensitizes retinal cells to protein homeostasis stress through p62-mediated caspase activation.
    Swetha Medchalmi, Zuberwasim Sayyad, Ghanshyam Swarup.
      M98K polymorphism of OPTN is significantly associated with glaucoma in certain populations. This raises the possibility that M98K-OPTN alone is not sufficient to cause glaucoma, and it may require cooperation with other genetic or environmental factors to induce glaucoma. Loss of vision in glaucoma occurs due to the degeneration of retinal ganglion cells. Here, we have tested the hypothesis that M98K-OPTN may enhance the sensitivity of retinal cells to protein homeostasis stress. For this purpose, we have used M98K-OPTN expressing and wild-type (WT)-OPTN expressing clones of retinal 661W cells. Upon induction of protein homeostasis stress by a proteasome inhibitor MG132 (1-2 μM), M98K-OPTN expressing cells showed reduced survival, and enhanced caspase-8, caspase-9, and caspase-3 activation in comparison with WT-OPTN expressing cells. Compared to WT-OPTN expressing cells, M98K-OPTN expressing cells showed enhanced formation of p62/SQSTM1-positive aggregates and enhanced p62 protein level under conditions of protein homeostasis stress. Knockdown of p62 resulted in reduced caspase-9, caspase-8, and caspase-3 activation in M98K-OPTN expressing cells treated with proteasome inhibitor. Our results suggest that M98K-OPTN modulates protein homeostasis stress-induced signalling that mediates p62-dependent caspase activation, which leads to enhanced sensitivity of M98K-OPTN expressing retinal cells to protein homeostasis stress.
    Keywords:  Glaucoma; Neurodegeneration; Optineurin; Protein aggregation; Protein homeostasis stress; p62/SQSTM1
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120064
  7. Neurobiol Dis. 2025 Sep 24. pii: S0969-9961(25)00336-5. [Epub ahead of print] 107119
    The alternative complement pathway drives neuroinflammation and neurodegeneration in mouse models of glaucoma and optic nerve injury.
    Cindy Hoppe, Ryo Mukai, Nasrin Refaian, Margarete Karg, Shintaro Shirahama, Maleeka Shrestha, Yinjie Guo, Amarachi Nwogu, Drenushe Krasniqi-Vanmeter, Volha V Malechka, Bruce R Ksander, Kip Connor, Meredith Gregory-Ksander.
      Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. Although elevated intraocular pressure (IOP) is a major risk factor, disease progression can occur despite normal IOP, highlighting the need for neuroprotective strategies beyond IOP reduction. Neuroinflammation has been implicated in glaucomatous neurodegeneration through complement system activation via the classical and lectin pathways. However, the role of the alternative pathway (AP), which functions as an amplification loop for central complement component 3 (C3) activation, in glaucoma is unclear. In this study, we investigated the role of the AP in glaucoma using a microbead-induced mouse model of glaucoma in mice deficient in either complement factor B (Cfb-/-), to selectively block the AP, or in C3 (C3-/-) to block all three complement pathways. Our results indicate that the AP is critical for glaucoma development, and blocking this pathway resulted in significant neuroprotection, preventing loss of RGCs, axons, and visual acuity, which coincided with reduced glial activation and inflammatory signaling. Blocking the AP provided comparable neuroprotection to blocking all three complement pathways, indicating that the AP amplification loop is an essential component of destructive neuroinflammation in glaucoma. Furthermore, blocking the AP also conferred neuroprotection in the optic nerve crush model, suggesting a broader role for AP in optic neuropathies. These findings establish the AP as a key driver of complement-mediated neurodegeneration in glaucoma and highlight the therapeutic potential of targeting the AP in glaucoma and other neurodegenerative diseases.
    Keywords:  Complement system; Glaucoma; Inflammation; Microglia; Neuroprotection
    DOI:  https://doi.org/10.1016/j.nbd.2025.107119
  8. Annu Rev Virol. 2025 Sep;12(1): 157-178
    Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
    Théo Defresne, Rodolphe Suspène, Jean-Pierre Vartanian.
      Mitochondria play a vital role in cellular metabolism, energy production, and immune signaling, making them key targets for viral manipulation. Viruses exploit mitochondrial functions to enhance replication and evade immune responses. They also disrupt mitochondrial dynamics by altering fission/fusion balance and modulating mitophagy, which is essential for mitochondrial quality control. Additionally, they reprogram mitochondrial metabolism, affecting pathways such as oxidative phosphorylation and glycolysis to support replication. Viruses regulate apoptosis, either inhibiting or activating mitochondria-mediated apoptosis to prolong host cell survival or facilitate viral spread. Viral infections also induce oxidative stress through reactive oxygen species generation, affecting cellular integrity. Furthermore, viruses manipulate mitochondrial antiviral immunity by degrading mitochondrial antiviral signaling protein and triggering the release of mitochondrial DNA, modulating immune responses. Understanding these interactions offers valuable insights into viral pathogenesis and presents therapeutic opportunities. Targeting mitochondrial dysfunction and enhancing antiviral immunity could provide new strategies to mitigate viral damage and enhance cellular resilience.
    Keywords:  antiviral immunity; metabolic pathways; mitochondria; mitochondrial dynamics; oxidative stress; virus
    DOI:  https://doi.org/10.1146/annurev-virology-092623-090901
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