bims-mideyd 2025-09-14 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2025–09–14
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Hormetic Effects of Curcumin in RPE Cells: SIRT1 and Caspase-3 Inactivation with Implications for AMD.
Specific Assay Protocols for Porcine Single-Eye Retinal Pigment Epithelium Concerning Oxidative Stress and Inflammation.
Light-emitting diode-derived blue light overexposure accelerates corneal endothelial cell aging by inducing abnormal ROS accumulation.
Tropism and Retinal Transduction Efficiency of Adeno-Associated Virus Serotypes in Mice.
Na-Cl Cotransporter (SLC12A3) Inhibition Exacerbates Age-Related Macular Degeneration Via the Nrf2/HO-1 Ferroptosis Pathway.
SIRT1 as a potential target for age-related eye diseases: mechanisms and therapeutic strategies.
Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.

Int J Mol Sci. 2025 Sep 03. pii: 8555. [Epub ahead of print]26(17):

Hormetic Effects of Curcumin in RPE Cells: SIRT1 and Caspase-3 Inactivation with Implications for AMD.

Jacopo Di Gregorio, Darin Zerti, Giulia Carozza, Annamaria Capozzo, Vincenzo Flati, Marco Feligioni, Rita Maccarone.

  Retinal Pigment Epithelium (RPE), a component of the blood-retinal barrier, plays a pivotal role in maintaining retinal homeostasis and visual function. Dysfunction of the RPE is an early event that triggers photoreceptor death, in Age-related Macular Degeneration (AMD), a multifactorial disorder primarily caused by an imbalance between endogenous antioxidant defenses and reactive oxygen species production. Our in vitro study investigated the hormetic effects of curcumin in human RPE cells (ARPE-19), focusing on its capability to modulate two enzymes related to the onset of AMD: Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase enzyme involved in cellular metabolism, aging, and stress response, and caspase-3, a crucial enzyme in programmed cell death. Curcumin exhibited classic hormetic doseresponses, with low concentrations (5-10 μM) providing cytoprotection while at high doses (≥20 μM) inducing toxicity. Under moderate oxidative stress, acetylated p53 was significantly reduced, indicating SIRT1 activation; curcumin 10 μM restored basal SIRT1 activity, while 5 µM did not. Both concentrations significantly decreased cleaved caspase-3 levels, demonstrating the anti-apoptotic effects of curcumin. Our results reveal curcumin's hormetic mechanisms of RPE protection and emphasize the critical importance of dose optimization within the hormetic window for AMD therapeutic development.

Keywords:  AMD; RPE; SIRT1; acetyl-p53; caspase-3; curcumin; oxidative stress

DOI:  https://doi.org/10.3390/ijms26178555
Int J Mol Sci. 2025 Aug 29. pii: 8434. [Epub ahead of print]26(17):

Specific Assay Protocols for Porcine Single-Eye Retinal Pigment Epithelium Concerning Oxidative Stress and Inflammation.

Philipp Dörschmann, Marie Prinz, Greta Schmitkall, Johann Roider, Alexa Klettner.

  The retinal pigment epithelium (RPE) is strongly involved in the pathogenesis of several retinal diseases, such as age-related macular degeneration (AMD). RPE models addressing specific pathological pathways are of high importance for understanding cellular pathomechanisms and pre-clinical screening of potential new therapeutics. The goal of this study is to establish standard operation protocols for single-eye porcine RPE preparation for AMD-relevant models of oxidative stress (RPE-Ox) and inflammation (RPE-Inf). Porcine primary RPE were prepared from one eye and seeded into one well of 12-well plates or, for polar differentiation, in transwell inserts. Different coatings (Poly-ᴅ-Lysine and laminin) and serum content of media (10%, 5%, and 1%) were tested to determine optimal culture parameters. For RPE-Ox, cells were treated with NaIO3, CoCl2, or erastin; cell viability (thiazolyl blue tetrazolium bromide, MTT), and gene expression (RT-qPCR) were determined. For RPE-Inf, cells were treated with lipopolysaccharide (LPS), polyinosinic/polycytidylic acid (Poly I:C), or tumor necrosis factor alpha (TNF-α); cell viability (MTT), cytokine secretion (ELISA), and gene expression (RT-qPCR) were determined. For transwell plates in RPE-Inf, cell viability (MTT), polar cytokine secretion (ELISA), gene expression (RT-qPCR), and transepithelial electrical resistance (TEER) for barrier assessment were conducted. For RPE-Ox, effective LD50 could be achieved by using 24 h stimulation with 25 µm erastin, seven days after preparation in 5% serum cultures, without coating. For gene expression assessment, the use of Poly-ᴅ-Lysine is recommended. For RPE-Inf, three days of LPS stimulation (1 µg/mL) showed effective cytokine activation with 5% serum on uncoated 12-well plates. Transwell plates are not recommended for cytokine secretion assessment. It can be used for cell barrier assays in which LPS also showed effective cell barrier decrease and gene expression assays. Two specific best practice protocols for the use of porcine single-eye cultures in AMD research concerning oxidative stress and inflammation with optimized parameters were established and are provided.

Keywords:  3R principle; age-related macular degeneration treatment; best practice protocol; inflammation; oxidative stress; primary cell culture; retinal pigment epithelium; single-eye cultures

DOI:  https://doi.org/10.3390/ijms26178434
J Photochem Photobiol B. 2025 Sep 01. pii: S1011-1344(25)00155-1. [Epub ahead of print]272 113252

Light-emitting diode-derived blue light overexposure accelerates corneal endothelial cell aging by inducing abnormal ROS accumulation.

Zhaolin Liu, Yiran Yang, Ke Yan, Jieli Wu, Xiang Lin, Liying Tang, Qingjian Li, Caihong Huang, Jiaoyue Hu, Zuguo Liu.

  Blue light, defined as short-wavelength visible light ranging from 400 to 500 nm, is recognized for its high energy within the visible light spectrum. The prevalent use of light-emitting diodes (LEDs) has significantly increased exposure to blue light. Corneal endothelial cells (CECs) playing a crucial role in maintaining corneal transparency to get clear visual field. However, the specific effects of blue light on corneal endothelium remain unclear. To investigate this, in vivo and in vitro models of LED blue light irradiation were established. We examined changes in CEC fate and indicators related to oxidative stress. Our findings revealed that blue light exposure led to increased production of ROS in CECs, causing oxidative stress primarily in mitochondria. This, in turn, resulted in cell senescence, dysfunction, and apoptosis, ultimately contributing to the aging of corneal endothelium with accelerated cell loss. Notably, the rise in ROS levels triggered the activation of the Nrf2 signaling pathway in the early stages. This activation was associated with protective effects on CECs and inhibition of cell senescence. Our study sheds light on the intricate relationship between blue light exposure, oxidative stress, and the fate of CECs, providing valuable insights into the potential mechanisms underlying corneal aging.

Keywords:  Aging; Blue light; Corneal endothelial cells; Oxidative stress; ROS; Senescence

DOI:  https://doi.org/10.1016/j.jphotobiol.2025.113252
Invest Ophthalmol Vis Sci. 2025 Sep 02. 66(12): 18

Tropism and Retinal Transduction Efficiency of Adeno-Associated Virus Serotypes in Mice.

Wenjing Wu, Joel McRae, Asa Brown, Martin-Paul Agbaga.

Purpose: Adeno-associated viruses (AAVs) have become the preferred vector for gene therapy in ophthalmology. However, requirements for specific cell surface receptors limit AAV-mediated retinal cell transduction efficiency. This led to the need to engineer novel AAV vectors for widespread retinal transduction and transgene expression. However, no comparative analyses of these novel AAV serotypes have been reported. Here, we compare the retinal transduction efficiency of four novel AAV serotypes in wild-type mice retina after intravitreal and subretinal injections.
Methods: In total, 1.0 µL each of the four different AAV/cytomegalovirus/enhanced green fluorescent protein (EGFP) synthetic serotypes (1 × 109 genome copies [GC]/eye) was delivered by intravitreal or subretinal injection into mouse eyes. Tropism of each serotype to efficiently transduce photoreceptor (PR) and retinal pigment epithelial (RPE) cells was examined by EGFP expression using fundoscopy and immunolabeling 1 and 2 months after administration. Retinal function was evaluated using electroretinography and optomotor kinetics.
Results: Fundoscopy and immunolabeling of EGFP in both subretinally and intravitreally injected AAV/DJ and AAV/DJ8 retinas showed the highest transduction efficiency. Compared to intravitreal delivery, all serotypes successfully transduced PR and RPE cells after subretinal injections. However, only intravitreally delivered AAV27m8, AAV/DJ, and AAV/DJ8 efficiently transduce PRs. AAV/DJ8 exhibited the highest PR and RPE transduction of the four serotypes. Visual function was unaffected, and adverse immunologic responses were not observed between the serotype and the PBS-injected eye.
Conclusions: Synthetic AAV serotypes differentially transduced PR and RPE cells depending on the delivery route. AAV/DJ8 exhibited the most efficient transduction of PR and RPE cells when injected intravitreally.

DOI: https://doi.org/10.1167/iovs.66.12.18
Invest Ophthalmol Vis Sci. 2025 Sep 02. 66(12): 24

Na-Cl Cotransporter (SLC12A3) Inhibition Exacerbates Age-Related Macular Degeneration Via the Nrf2/HO-1 Ferroptosis Pathway.

Chengming Chen, Tingke Xie, Huan Zhang, Lifu Chang, Yanyan Lan, Chao Fan, Dongyu Wei, Xiaolan Wang, Sida Liu, Yixuan Chen, Yuhao Chen, Xuejiao Wang, Xiaolong Yan, Lei Shang, Liyuan Tao, Jing Han.

Purpose: To explore the causal links between antihypertension drugs usage and age-related macular degeneration (AMD).
Methods: Multiple genetic analyses, including summary data-based Mendelian randomization (SMR), traditional MR, and colocalization analysis, were used to explore the causal associations between antihypertension drugs and AMD. Clinical data from the UK Biobank and the National Health and Nutrition Examination Survey (NHANES) was applied to refined risk assessment of specific antihypertensive medications in the context of AMD development. In vitro and in vivo oxidative stress models, mediated by NaIO3, were utilized to study the impact of specific antihypertensive drugs and target genes on AMD pathogenesis.
Results: Genetic analyses substantiated the causal relationship between increased SLC12A3 expression and a lowered AMD risk. Colocalization analysis supported the shared causal attributes between SLC12A3 expression and AMD. Cross-sectional analysis results based on UK Biobank indicated that AMD risk was significantly lower in participants taking thiazide diuretics with other antihypertensives or not on antihypertensives compared to those on thiazides alone. The results based on NHANES support the above results. In vivo and in vitro experiments showed that thiazide diuretics worsened retinal damage in AMD mouse models, and SLC12A3 knockdown disrupted the balance of oxidative stress in retinal pigment epithelium (RPE) cells. Further molecular mechanism experiments showed that SLC12A3 knockdown promoted retinal degeneration by regulating RPE ferroptosis through activation of the Nrf2/HO-1 pathway.
Conclusions: Our study underscores a notable causal association between thiazide diuretic use and AMD risk and reveals a potential mechanism by which inhibition or downregulation of SLC12A3 (sodium-chloride cotransporter [NCC]) contributes to AMD progression. However, deeper exploration is needed to enhance the accuracy and validity of our findings.

DOI: https://doi.org/10.1167/iovs.66.12.24
Hum Cell. 2025 Sep 07. 38(6): 155

SIRT1 as a potential target for age-related eye diseases: mechanisms and therapeutic strategies.

Huirui Liu, Yuting Ouyang, Hongyan Ge.

  Age-related eye diseases (AREDs) are the leading cause of visual impairment in the elderly, affecting the structure of the anterior and posterior segments of the eye, significantly reducing the quality of life of patients, and even leading to irreversible blindness. Typical AREDs include age-related cataract (ARC), dry eye disease (DED), age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), the global prevalence of which continues to rise, becoming a serious public health concern. SIRT1 is an NAD + dependent deacetylase, which plays an important physiological regulatory role in ocular tissues, mainly affecting gene expression and various cellular processes by regulating the acetylation status of substrate proteins. Studies have shown that SIRT1 plays a key role in oxidative stress, inflammation, autophagy, apoptosis and metabolism, and its expression or activity decreases can accelerate cell senescence and promote the occurrence and development of AREDs. In addition, SIRT1 expression levels and changes in its activity have been shown to be strongly associated with AREDs, making it a potential target for disease intervention and therapy. Therefore, this review systematically summarizes the biological role and regulatory mechanism of SIRT1 in AREDs, and explored its potential value as a therapeutic target, providing theoretical basis for future drug development and clinical transformation.

Keywords:  Age-related eye diseases; Aging; Cell senescence; Oxidative stress; SIRT1

DOI:  https://doi.org/10.1007/s13577-025-01285-w
Exp Eye Res. 2025 Sep 08. pii: S0014-4835(25)00403-8. [Epub ahead of print] 110632

Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.

Hetong Sun, Bin Li, Yu Gu, Fei Li, Guohu Di, Peng Chen.

  Mitochondria play a crucial role in energy production and are intimately associated with ocular function. Mitochondrial dysfunction can trigger oxidative stress and inflammation, adversely affecting key ocular structures such as the lacrimal gland, lens, retina, and trabecular meshwork. This dysfunction may compromise the barrier properties of the trabecular meshwork, impeding aqueous humour outflow, elevating intraocular pressure, and resulting in optic nerve damage and primary open-angle glaucoma. Additionally, impaired mitochondrial homeostasis can contribute to dry eye, cataracts, and age-related macular degeneration (AMD) by disrupting the function of the lacrimal gland, lens, and macula. Imbalanced mitochondrial homeostasis primarily involves four pathological features: disruption of mitochondrial quality control, mitochondrial damage (inducing inflammation), excessive production of mitochondrial reactive oxygen species (ROS) (initiating oxidative stress), and disturbances in mitochondrial calcium (Ca2+) homeostasis. Oxidative stress and inflammation are central mechanisms of cellular injury. Pharmacological strategies aimed at reducing excessive ROS, restoring redox balance, and mitigating oxidative and inflammatory damage show therapeutic promise. Moreover, enhancing mitochondrial function through pharmacological agents, replacing damaged mitochondria, and promoting mitochondrial rejuvenation represent emerging treatment avenues. This review explores the relationship between mitochondrial dysfunction and ocular diseases such as dry eye, glaucoma, cataracts, and AMD, with a focus on associated mechanisms and potential therapeutic interventions.

Keywords:  AMD; Cataracts; Dry eye; Glaucoma; Mitochondrial Dysfunction; Oxidative Stress; Targeted Therapy

DOI:  https://doi.org/10.1016/j.exer.2025.110632