bims-mideyd 2026-08-30 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–08–30
eight papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Dual-restricted AAV gene delivery via suprachoroidal administration mediates precision RPE SOCS3 restoration for dry age-related macular degeneration.
FOXO6 inhibits SMURF2-mediated ubiquitination and degradation of NR4A1 to promote retinal pigment epithelial cell ferroptosis in diabetic retinopathy.
Glucocorticoid-induced RPE injury in ARPE-19 cells: association with excessive autophagy and AMPK/mTOR signaling.
Epigallocatechin gallate protects ARPE-19 cells in vitro and the retina in vivo by suppressing NF-κB p65-mediated ferroptosis.
Mitochondrial outer membrane protein FUNDC2 contributes to ferroptosis as a potential upstream regulator in retinitis pigmentosa.
Resveratrol mitigates hypoxia-induced mitochondrial oxidative damage and apoptosis via inhibition of TRPA1 channel in retinal pigment epithelial cells.
Blocking the RhoA/ROCK/cofilin/F-actin Pathway via Y27632 Protects Against MERTK-deficient Retinal Degeneration and Visual Function Impairment.
Enhancing lysosome function via TFEB activation reduces lipofuscin-like granules in the retinal pigment epithelium.

J Control Release. 2026 Aug 24. pii: S0168-3659(26)00693-0. [Epub ahead of print]399(Pt A): 115289

Dual-restricted AAV gene delivery via suprachoroidal administration mediates precision RPE SOCS3 restoration for dry age-related macular degeneration.

Yiquan Zhang, Fuxiao Luan, Jing Feng, Wenqiang Sun, Yong Tao.

  Dry age-related macular degeneration (dAMD) is a leading cause of irreversible vision loss, driven by chronic oxidative stress and inflammation in the retinal pigment epithelium (RPE). Disruption of key negative regulators of the JAK-STAT pathway, particularly SOCS3, contributes to this oxidative-inflammatory cascade. To address this, we developed a dual-restricted ocular gene delivery platform that combines suprachoroidal administration with an RPE-specific Best1 promoter, enabling localized, durable, and cell-restricted SOCS3 expression. Comparative analysis showed that intravitreal injection poorly transduced the RPE, whereas suprachoroidal delivery improved AAV access to the RPE/outer retinal region, and the Best1 promoter further restricted expression to RPE cells, reducing neural retinal off-target expression. In vitro, SOCS3 restoration suppressed STAT3 activation, inflammatory cytokine release, reactive oxygen species accumulation, mitochondrial disruption, and barrier impairment. In vivo, the dual-restricted system achieved long-term, ocular-localized expression for at least six months, reducing microglial/macrophage activation, inflammation, oxidative stress, and apoptosis, thereby preserving outer retinal architecture. Ocular and systemic safety assessments detected no overt toxicity under the tested conditions. Together, these findings support suprachoroidal AAV-Best1-SOCS3 delivery as a dual-restricted platform for localized modulation of oxidative-inflammatory retinal degeneration and warrant further preclinical evaluation.

Keywords:  Dry age-related macular degeneration; Dual-restricted gene delivery; Inflammation; RPE-specific Best1 promoter; Reactive oxygen species; SOCS3-STAT3 axis; Suprachoroidal delivery

DOI:  https://doi.org/10.1016/j.jconrel.2026.115289
J Cell Commun Signal. 2026 Sep;20(3): e70108

FOXO6 inhibits SMURF2-mediated ubiquitination and degradation of NR4A1 to promote retinal pigment epithelial cell ferroptosis in diabetic retinopathy.

Qiao Chen, Bo Su, Ke Xu, Liang Li, Changzheng Chen.

  Diabetic retinopathy (DR) is the main cause of vision loss, with retinal pigment epithelial (RPE) cell dysfunction as a key contributor. Ferroptosis is implicated in RPE injury under hyperglycemia; however, its upstream regulatory mechanisms remain unclear. High glucose (HG)-induced human RPE ARPE-19 cells and a diabetic mouse model were used. Ferroptosis was assessed through biochemical assays, Western blot, fluorescence probes, and histological staining. Protein interactions and transcriptional regulation were examined using Co-IP, glutathione S-transferase pull-down, ChIP, and luciferase reporter assays. Immunofluorescence staining was used as key indicator expression in retinal tissues. Nuclear receptor 4A1 (NR4A1) expression was upregulated under HG-induced ARPE-19 cells. NR4A1 knockdown alleviated HG-induced iron accumulation, lipid peroxidation, and ferroptosis marker changes. Mechanistically, SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) interacted with NR4A1 and promoted its ubiquitination and degradation. Forkhead box O6 (FOXO6) was upregulated by HG and repressed SMURF2 transcription. SMURF2 overexpression mitigated HG-induced ARPE-19 ferroptosis and retinal injury in DR mice, an effect reversed by NR4A1 co-overexpression. SMURF2 knockdown reversed the effect of FOXO6 knockdown on HG-induced ferroptosis in ARPE-19 cells and retinal injury in DR mice. The FOXO6-SMURF2-NR4A1 axis critically regulates ferroptosis in RPE cells during DR.

Keywords:  Forkhead box O6; SMAD‐specific E3 ubiquitin protein ligase 2; diabetic retinopathy; ferroptosis; nuclear receptor subfamily 4 group A member 1; ubiquitination

DOI:  https://doi.org/10.1002/ccs3.70108
Int J Ophthalmol. 2026 ;19(9): 1657-1666

Glucocorticoid-induced RPE injury in ARPE-19 cells: association with excessive autophagy and AMPK/mTOR signaling.

Wen-Xue Guan, Yue Guo, Si-Tong Chen, Zhi-Ming Liu, Yao-Yao Sun, Ming-Wei Zhao.

   AIM: To investigate whether excessive glucocorticoid (GC) exposure disrupts retinal pigment epithelial (RPE) homeostasis through glucocorticoid receptor (GR)-dependent autophagy hyperactivation.
METHODS: Human retinal pigment epithelial cell line (ARPE-19 cells) were exposed to GC (0-100 µmol/L, 48h). GR subcellular localization was analyzed via mitochondrial fractionation and immunofluorescence. Functional assessments included barrier integrity [zonula occludens-1 (ZO-1) immunostaining], phagocytic capacity (FluoSpheres™-labeled photoreceptor outer segment uptake), and ultrastructural analysis (transmission electron microscopy, TEM). Autophagic flux was quantified using mCherry-green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (LC3) B reporters. Molecular mechanisms were probed through AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway activity and autophagic flux assessed by LC3-II levels. GR dependency was confirmed using the antagonist RU486, and cell-type specificity was assessed using mouse photoreceptor (661W) cells.
RESULTS: GC induced GR upregulation and mitochondrial translocation in a dose- and time-dependent manner, correlating with pathological autophagy activation. Key findings included: 1) tight junction disruption, evidenced by ZO-1 fragmentation, 2) reduction in phagocytic uptake efficiency, 3) mitochondrial shrinkage and autolysosome accumulation (TEM), 4) altered AMPK/mTOR signaling (p-AMPK up, p-mTOR down) associated with autophagosome formation, 5) elevated LC3-II levels confirming excessive autophagic flux. Critically, all GC-induced effects, including GR upregulation, signaling changes, and increased autophagy, were abolished by GR antagonism with RU486.
CONCLUSION: This study shows that GR-dependent GC exposure induces autophagic flux with ultrastructural evidence suggestive of mitochondria-targeted autophagy and alters AMPK/mTOR signaling, correlating with RPE barrier collapse and phagocytic failure, a possible link to steroid-associated central serous chorioretinopathy (CSC).

Keywords:  AMPK/mTOR; autophagy; central serous chorioretinopathy; glucocorticoid; retinal pigment epithelial cells

DOI:  https://doi.org/10.18240/ijo.2026.09.01
Exp Eye Res. 2026 Aug 25. pii: S0014-4835(26)00370-2. [Epub ahead of print]272 111214

Epigallocatechin gallate protects ARPE-19 cells in vitro and the retina in vivo by suppressing NF-κB p65-mediated ferroptosis.

Xiaoyang Chen, Miao Han, Yiwen An, Shuaishuai Zhang, Mengjia Liu, Yuxuan Wang, Shengyan Zhao, Ziyi Wang, Yuanyuan Zhang.

  The accumulation of ferrous ions and resulting oxidative stress within the retinal pigment epithelium triggers ferroptosis, leading to photoreceptor degeneration in dry age-related macular degeneration (dAMD), which is a disease currently without effective therapy. As ferroptosis has been identified as a molecular target of epigallocatechin-3-gallate (EGCG) in other diseases, this study aimed to investigate the protective role of EGCG and its mechanism against ferroptosis in NaIO3-induced ARPE-19 cell and RPE injury. We observed that iron overload disrupts iron homeostasis in both cellular and animal models, leading to RPE damage via ferroptosis activation. In ARPE-19 cells, EGCG attenuated NaIO3-induced injury by reducing Fe2+, MDA, and LDH levels, increasing GSH content, and upregulating SLC7A11 and GPX4 expression, effects which were equivalent to those produced by Fer-1. Mechanistically, EGCG exerted its anti-ferroptotic effect by binding strongly to NF-κB p65 and inhibiting its activation, consistent with the effects of the NF-κB inhibitor QNZ and NF-κB p65 silencing. In a dAMD model, EGCG administration suppressed ferroptosis, downregulated NF-κB p65 expression, and ameliorated RPE damage. In conclusion, these findings suggest that EGCG alleviates RPE damage associated with NF-κB p65-mediated ferroptosis, providing new insights into AMD pathogenesis and a promising therapeutic strategy.

Keywords:  ARPE-19; Age-related macular degeneration; Epigallocatechin gallate; Ferroptosis; NF-κB p65

DOI:  https://doi.org/10.1016/j.exer.2026.111214
Int J Ophthalmol. 2026 ;19(9): 1667-1675

Mitochondrial outer membrane protein FUNDC2 contributes to ferroptosis as a potential upstream regulator in retinitis pigmentosa.

Jie-Yu Chen, Ya-Fen Huang, Yu Hong.

   AIM: To investigate the key role of the mitochondrial outer membrane protein FUN14 domain-containing 2 (FUNDC2) in retinal pigment epithelium (RPE) ferroptosis during retinitis pigmentosa (RP) progression.
METHODS: Unbiased label-free proteomics was employed to identify differentially expressed proteins in the RPE of a sodium iodate (SI)-induced rat model. In vitro experiments were conducted using human retinal pigment epithelial (ARPE)-19 cells. The effects of SI treatment and FUNDC2 knockdown on cell viability and the expression of ferroptosis-protective molecules, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), and solute carrier family 25 member 11 (SLC25A11) were evaluated.
RESULTS: Proteomic analysis revealed that FUNDC2 was significantly upregulated in the RPE of SI-induced rats. In ARPE-19 cells, SI treatment significantly increased FUNDC2 expression while decreasing the levels of ferroptosis-protective molecules. Functional experiments demonstrated that knocking down FUNDC2 effectively rescued SI-induced loss of cell viability and restored GPX4 expression.
CONCLUSION: These findings provide the first evidence that FUNDC2 acts as a potential upstream regulator of RPE ferroptosis in RP, at least partially by negatively regulating GPX4. Consequently, FUNDC2 is a potential therapeutic target for the future treatment of RP.

Keywords:  FUNDC2; ferroptosis; retinal pigment epithelium; retinitis pigmentosa; sodium iodate

DOI:  https://doi.org/10.18240/ijo.2026.09.02
Int J Ophthalmol. 2026 ;19(9): 1676-1686

Resveratrol mitigates hypoxia-induced mitochondrial oxidative damage and apoptosis via inhibition of TRPA1 channel in retinal pigment epithelial cells.

Mehmet Argun, Mustafa Nazıroğlu.

   AIM: To investigate the modulator action of resveratrol (RSV) through the suppression of transient receptor potential ankyrin 1 (TRPA1) on the hypoxia (HPO)-caused oxidative degeneration and apoptosis in human retinal pigment epithelial cells (ARPE19).
METHODS: The control (CNT), RSV (50 µmol/L for 24h), HPO (200 µmol/L CoCl2 for 24h), and HPO+RSV groups were induced in the ARPE19. Apoptosis, caspases (caspases 3, 8, and 9), oxidants [lipid peroxidation, oxygen free radical (OFR), and dysfunction of mitochondrial membrane], antioxidants (glutathione and glutathione peroxidase), Ca2+, Zn2+ levels, live cell number and percentage were all measured in the cells of four groups.
RESULTS: The HPO increased Ca2+ and Zn2+ fluorescence intensity in the cells. It also upregulated the apoptosis, caspases, and oxidant indicators while downregulating the antioxidants, and the count of live cells. TRPA1 agonist (cinnamonaldehyde) further upregulated these indicators (all P<0.05). When the HPO-induced increase in TRPA1 activation was treated with RSV and the TRPA1 antagonist (AP18), cell viability and antioxidants rose while the oxidant and apoptotic indicators decreased due to TRPA1 suppression (P<0.05).
CONCLUSION: HPO exposure through TRPA1-mediated Ca2+ signaling, induces mitochondrial oxidative cell cytotoxicity and death, which may offer a treatment option for HPO-induced retinal disorders linked to increased OFR and Ca2+ influx.

Keywords:  TRPA1 channel; hypoxia; oxidative cytotoxicity; resveratrol; retinal pigment epithelial cells

DOI:  https://doi.org/10.18240/ijo.2026.09.03
Curr Med Chem. 2026 Aug 11.

Blocking the RhoA/ROCK/cofilin/F-actin Pathway via Y27632 Protects Against MERTK-deficient Retinal Degeneration and Visual Function Impairment.

Lujia Feng, Ting Zhang, Yong Du, Yingyan Qin, Linbin Zhou, Bingyu Bai, Manjuan Peng, Lu Chen, Jin Ma, Shaochong Zhang.

   INTRODUCTION: Retinitis pigmentosa (RP) is the most common inherited neurodegenerative retinal disease. Mer receptor tyrosine kinase (MERTK) mutations are associated with severe RP and dysfunction of the RPE. Previous studies have shown that MERTK and the Rho-associated coiled-coil-containing kinases (ROCK) pathway are involved in phagocytosis. However, the specific role of the ROCK pathway in the context of MERTK-associated RP needs to be revealed.
METHODS: We established an in vitro RP cellular model via MERTK depletion in human primary retinal pigment epithelium (HsRPE) cells by siRNAs, and RCS rats with spontaneous Mertk mutations were used as RP experimental animal models. Cell viability, apoptosis, phagocytosis, and visual function were measured by MTT, TUNEL and Annexin V/propidium iodide staining, phagocytosis assays and transmission electron microscopy, and electroretinography, respectively. The expression of RhoA, ROCK, Factin, and cofilin was determined by quantitative real-time PCR, western blotting, or immunofluorescence staining.
RESULTS: MERTK knockdown substantially impaired cell survival, promoted apoptosis, and suppressed phagocytosis in HsRPE cells. In RCS rats, Mertk mutations impaired phagocytosis, promoted apoptosis of the RPE, and damaged visual functions. Silencing MERTK upregulated the phosphorylation of RhoA, ROCK2, and cofilin and decreased F-actin expression in HsRPE cells. Blocking the RhoA/ROCK axis by a selective ROCK inhibitor, Y27632, rescued the MERTK depletion-induced phagocytic dysfunction and apoptosis of HsRPE cells and rat RPE.
DISCUSSION: Our results collectively indicate that MERTK maintains RPE survival and phagocytosis via regulating the RhoA/ROCK/cofilin/F-actin axis.
CONCLUSION: This study demonstrates that MERTK deficiency impairs RPE phagocytosis and promotes cell apoptosis, leading to retinal degeneration and visual dysfunction. These findings provide new insight into RP pathogenesis and thereby offer valuable references for future drug development.

Keywords:  MERTK; Retinitis pigmentosa; RhoA/ROCK pathway; phagocytosis; retinal pigment epithelium.

DOI:  https://doi.org/10.2174/0109298673436432260728094713
Exp Eye Res. 2026 Aug 24. pii: S0014-4835(26)00371-4. [Epub ahead of print] 111215

Enhancing lysosome function via TFEB activation reduces lipofuscin-like granules in the retinal pigment epithelium.

Ana S Falcão, Mafalda Lopes-da-Silva, Pedro Antas, Cristina Escrevente, Margarida Pedro, Beatriz Felgueiras, Beatriz Caires, Rita Coelho, Inês S Ferreira, Inês P Santos, Thomas Ciossek, Paul Nicklin, Sandra Tenreiro, Miguel C Seabra.

  Age-related macular degeneration (AMD) is the most common blinding disease in the western world and is currently incurable. Although the exact causes of AMD are not clear, the primary origin of pathology appears to be the aged retinal pigment epithelium (RPE) exhibiting signs of lysosomal dysfunction and oxidative damage. RPE is responsible for the daily digestion of photoreceptor outer segments (POS), imposing a heavy continuous burden on the lysosomal network. A cellular model of RPE lysosomal dysfunction can be achieved by feeding RPE with a single pulse of POS, leading to the accumulation of autofluorescence granules (AFG), similar to lipofuscin in vivo. Here we show that synchronous phagocytosis of POS leads to early transient mTOR activation followed by inhibition in late phagosome maturation. One of its substrates, the transcription factor EB (TFEB) increases during phagosome maturation albeit mostly in its inactive phosphorylated form. We questioned whether modulation of the mTOR/TFEB axis could improve POS clearance and hence reduce AFG load. Treatment of POS-fed cells after the appearance of AFGs with rapamycin, an mTORC1 inhibitor results in ∼30% reduction of AFG load. This effect is dependent on active lysosomal enzymes and induction of active dephosphorylated TFEB with consequent activation of GADD34 and lysosomal biogenesis. As a proof of concept, we show that overexpressing a constitutively active form of unphosphorylated TFEB dramatically reduces POS-dependent AFG accumulation. Overall, this study suggests that viral or pharmacological approaches activating the TFEB pathway in the RPE could be beneficial as cell-protective treatment of early/intermediate cases of AMD, acting to delay progression of the disease.

Keywords:  TFEB; autofluorescent granules; lysosomal dysfunction; mTOR; photoreceptor outer segments phagocytosis

DOI:  https://doi.org/10.1016/j.exer.2026.111215