bims-mideyd 2025-11-30 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2025–11–30
six papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

EPO-R76E Enhances Retinal Pigment Epithelium Viability Under Mitochondrial Oxidative Stress Induced by Paraquat.
ASNS Regulates H2O2-Induced Senescence, Oxidative Stress, and Glucose Metabolism in ARPE-19 Cells by Modulating USP13 Expression.
Protective role of Oxyresveratrol against NaIO3-induced oxidative stress in RPE cells via targeting NRF2-mediated ferroptosis in vitro and in vivo.
Activation of GSDME by all-trans-retinal increases sensitivity to photoreceptor ferroptosis.
Nrf2 Activated by PD-MSCs Attenuates Oxidative Stress in a Hydrogen Peroxide-Injured Retinal Pigment Epithelial Cell Line.
RPGRORF15 Mutations Disrupt Lysosomal Lipid Metabolism in Retinal Pigment Epithelium Cells and Cause Retinitis Pigmentosa.

Cells. 2025 Nov 14. pii: 1794. [Epub ahead of print]14(22):

EPO-R76E Enhances Retinal Pigment Epithelium Viability Under Mitochondrial Oxidative Stress Induced by Paraquat.

Jemima Alam, Alekhya Ponnam, Arusmita Souvangini, Sundaramoorthy Gopi, Cristhian J Ildefonso, Manas R Biswal.

  Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, primarily driven by oxidative stress-induced degeneration of retinal pigment epithelium (RPE). Erythropoietin (EPO), a hematopoietic cytokine with neuroprotective properties, has been shown to reduce apoptosis and retinal degeneration. In this study, we examined the cytoprotective role of a non-erythropoietic EPO variant, EPO-R76E, in suppressing oxidative stress and mitochondrial dysfunction related to oxidative stress in RPE cells. Stable ARPE-19 cell lines expressing EPO-R76E were generated via lentiviral transduction and exposed to paraquat to induce oxidative stress. Oxidative stress was induced using paraquat. EPO-R76E expression conferred increased cell viability and resistance to mitochondrial damage, as assessed by cytotoxicity assays. Western blot analysis revealed reduced expression of ferritin and p62/SQSTM1, diminished activation of p-AMPK and NRF2, and restoration of GPX4 levels, indicating enhanced antioxidant defenses. Moreover, intracellular iron accumulation and reactive oxygen species were significantly reduced in EPO-R76E-expressing cells exposed to paraquat. These findings suggest that EPO-R76E promotes mitochondrial homeostasis and modulates oxidative stress pathways. Our study positions EPO-R76E as a promising therapeutic candidate for halting RPE degeneration in AMD.

Keywords:  ARPE-19; RPE; antioxidants; erythropoietin; growth factors; mitochondrial dysfunction; paraquat; retinal degeneration

DOI:  https://doi.org/10.3390/cells14221794
Biofactors. 2025 Nov-Dec;51(6):51(6): e70057

ASNS Regulates H2O2-Induced Senescence, Oxidative Stress, and Glucose Metabolism in ARPE-19 Cells by Modulating USP13 Expression.

Xiangyang Xin, Xin Zhao, Xiaobo Han, Wenhan Pu.

  Age-related macular degeneration (AMD) is a common degenerative disease of the eye that ultimately leads to irreversible vision loss. Asparagine synthase (ASNS) is an aminotransferase, and its low expression is associated with retinal damage. The present study centered on the protective effect of ASNS on retinal epithelial cells. We found that in the AMD cell model, overexpression of ASNS reduced SA-β-gal staining and ROS production, and increased cell viability in H2O2-treated ARPE-19 cells. In addition, overexpression of ASNS increased glucose consumption, lactate production, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR) and enhanced the expression of glycolytic markers. Molecular mechanistic studies revealed that ASNS was highly bound to USP13 protein and increased USP13 expression. Furthermore, ASNS protected the retinal epithelium from oxidative stress damage in an animal model of AMD. Taken together, these findings suggest that the ASNS/USP13 axis plays an important regulatory role in AMD development. Our findings not only emphasized the understanding of the role of glucose metabolism in AMD, but also identified a promising target for future AMD therapy.

Keywords:  ARPE‐19 cells; ASNS; USP13; age‐related macular degeneration; glycolysis

DOI:  https://doi.org/10.1002/biof.70057
Eur J Pharmacol. 2025 Nov 25. pii: S0014-2999(25)01156-2. [Epub ahead of print] 178402

Protective role of Oxyresveratrol against NaIO3-induced oxidative stress in RPE cells via targeting NRF2-mediated ferroptosis in vitro and in vivo.

Chih-Chun Chuang, Yong-Syuan Chen, Wei-Yang Lu, Shih-Chi Su, Ting-Yu Liao, Shun-Fa Yang, Yi-Hsien Hsieh.

  Age-related macular degeneration (AMD) is a chronic retinal disorder that occurs when oxidative damages are gradually accumulated to the center of retina. Oxyresveratrol (OxyR), a naturally occurring stilbene found in many plants, has been reported to exhibit anti-inflammatory and anti-oxidative activities. To fill this gap, we explored the effect of OxyR on retinal pigment epithelial cells in response to oxidative stress and on a mouse model of AMD and further dissected the molecular mechanism underlying OxyR's actions. In this study, we demonstrated that OxyR efficiently impeded both apoptosis and ferroptosis of a human ARPE-19 cells induced by sodium iodate (NaIO3). Such protective effect of OxyR on NaIO3-induced ARPE-19 cells was accompanied with altered expression levels of NRF2, KEAP1, and several ferroptosis-related proteins. Moreover, OxyR treatment, coupled with silencing of NRF2, ferroptosis inhibitor (ferrostatin-1) or depletion of ROS, enhanced the protection of ARPE-19 cells from NaIO3-induced damages. Consistently, oral gavage of OxyR restored the reduction of retinal thickness and attenuated the upregulation of NRF2 in retinal pigment epithelium layers of NaIO3-treated mice. These results demonstrated that OxyR mitigates NaIO3-induced ARPE19 cell death via targeting NRF2-ferroptosis signaling. Our findings provided potential avenues for the use of OxyR in controlling AMD.

Keywords:  Age-related macular degeneration; Ferroptosis; Oxidative stress; Oxyresveratrol; Retinal pigment epithelium; Sodium iodate

DOI:  https://doi.org/10.1016/j.ejphar.2025.178402
Int J Biol Sci. 2025 ;21(15): 7029-7042

Activation of GSDME by all-trans-retinal increases sensitivity to photoreceptor ferroptosis.

Bo Yang, Kunhuan Yang, Yuling Chen, Ruitong Xi, Jiahuai Han, Shiying Li, Jingmeng Chen, Yalin Wu.

  Impaired clearance of all-trans-retinal (atRAL) due to visual cycle dysfunction contributes to photoreceptor atrophy, a key pathological hallmark of Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (AMD). Prior studies have shown that light-induced atRAL accumulation promotes ferroptosis and activates gasdermin E (GSDME) in retinal photoreceptors of Abca4-/-Rdh8-/- mice, a model for STGD1 and dry AMD that exhibits visual cycle disorders. However, the role of GSDME in photoreceptor ferroptosis remains unclear. In this study, we revealed that GSDME activation by atRAL triggered photoreceptor ferroptosis and retinal atrophy via mitochondrial damage and oxidative stress. Knocking out GSDME significantly attenuated light-induced photoreceptor ferroptosis and retinal degeneration in Abca4-/-Rdh8-/- mice. Moreover, deleting the Gsdme gene in photoreceptor cells prevented atRAL-induced ferroptosis by inhibiting mitochondrial reactive oxygen species (mitoROS) production, iron overload, and lipid peroxidation. Notably, treatment with the mitoROS scavenger MitoTEMPO mitigated ferroptosis in atRAL-loaded photoreceptor cells and dramatically relieved photoreceptor ferroptosis and retinal degeneration in light-exposed Abca4-/-Rdh8-/- mice. We found that both GSDME elimination and MitoTEMPO treatment repressed atRAL-induced photoreceptor ferroptosis and retinal atrophy by inactivating the mitoROS-induced oxidative stress. In conclusion, GSDME-mediated photoreceptor ferroptosis is crucial for inducing structural and functional damage of the retina in retinopathies caused by atRAL accumulation, thereby providing new therapeutic insights for the prevention and treatment of STGD1 and dry AMD.

Keywords:  GSDME; all-trans-retinal; ferroptosis; macular degeneration; photoreceptor

DOI:  https://doi.org/10.7150/ijbs.114187
Antioxidants (Basel). 2025 Oct 25. pii: 1279. [Epub ahead of print]14(11):

Nrf2 Activated by PD-MSCs Attenuates Oxidative Stress in a Hydrogen Peroxide-Injured Retinal Pigment Epithelial Cell Line.

Se Jin Hong, Dae-Hyun Lee, Jeong Woo Choi, Hankyu Lee, Youngje Sung, Gi Jin Kim.

  Age-related macular degeneration (AMD) is a retinal degenerative disease caused by oxidative stress. Thus, we aimed to reduce oxidative stress through the use of placenta-derived mesenchymal stem cells (PD-MSCs). To induce oxidative stress in ARPE-19 cells, we treated them with 200 µM hydrogen peroxide (H2O2) for 2 h and then cocultured them with PD-MSCs. The dissociation of the KEAP1/Nrf2 complex, along with the expression of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), increased in the coculture group compared with the H2O2 treatment group (* p < 0.05). The expression levels of antioxidant genes increased in the cocultured group compared with those in the H2O2 treatment group (* p < 0.05), whereas the ROS levels decreased in the cocultured group (* p < 0.05). Additionally, both the expression of mitochondrial dynamics markers and the mitochondrial membrane potential increased when the cells were cocultured with PD-MSCs (* p < 0.05). PD-MSC cocultivation decreased the expression levels of lipoproteins (* p < 0.05). Finally, we confirmed that PD-MSCs promoted the expression of RPE-specific genes in H2O2-injured ARPE-19 cells (* p < 0.05). These findings suggest a new aspect of stem cell treatment for AMD induced by oxidative stress.

Keywords:  ARPE-19; KEAP1; Nrf2; age-related macular degeneration; mitochondrial dynamics; oxidative stress; placenta-derived mesenchymal stem cells

DOI:  https://doi.org/10.3390/antiox14111279
Invest Ophthalmol Vis Sci. 2025 Nov 03. 66(14): 61

RPGRORF15 Mutations Disrupt Lysosomal Lipid Metabolism in Retinal Pigment Epithelium Cells and Cause Retinitis Pigmentosa.

Mengmeng Ren, Xiang Chen, Pan Gao, Yukan Huang, Shanshan Yu, James Reilly, Kui Sun, Yunqiao Han, Hualei Hu, Pei Li, Jiong Luo, Liyan Dai, Yuejie Zhu, Qunwei Lu, Xinhua Shu, Shusheng Wang, Xiang Ren, Zhaohui Tang, Mugen Liu.

Purpose: X-linked retinitis pigmentosa (XLRP) is a severely blinding retinal disease, most of which are due to mutations in retinitis pigmentosa GTPase regulator (RPGR). The patients with RPGR mutations exhibit severe retinal pigment epithelium (RPE) atrophy and photoreceptor degeneration. Previous research mainly focused on the role of RPGR in the connecting cilia of photoreceptors. However, the mechanism underlying RPE deficiency in patients remains unclear. Moreover, the function of RPGR in RPE cells has not been investigated.
Methods: To investigate the mechanisms underlying RPE atrophy and the role of RPGR in RPE cells, the rpgra-/- zebrafish, human RPE cell line RPE-1, and ARPE-19 were utilized. Histological analysis, immunofluorescence, and lipid staining were used to investigate the morphology of photoreceptor and RPE cells, as well as the accumulation of lipid droplets (LDs) in RPE cells. FITC-labeled OS were used to evaluate the engulfment and degradation capabilities of RPE cells.
Results: The zebrafish homolog of human RPGRORF15, rpgra, is expressed in RPE cells. The rpgra-/- zebrafish exhibits RPE atrophy, followed by photoreceptor degeneration. Loss of rpgra impairs lysosome formation in RPE cells, leading to defective RPE phagocytosis. This triggers lipid metabolism disorders, ultimately causing RPE and retinal degeneration.
Conclusions: RPGRORF15 is essential for maintaining lysosome function and lipid metabolism homeostasis in RPE cells. This finding elucidates the previously unrecognized role of RPGRORF15 in RPE cells. This study provides new insights into the mechanisms underlying RPGR-associated retinal diseases and offers potential therapeutic approaches.

DOI: https://doi.org/10.1167/iovs.66.14.61