bims-mideyd 2026-06-28 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–06–28
seven papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Tetrahydrocurcumin Attenuates NaIO3-Induced Retinal Oxidative Injury via Suppression of NOX2-Derived ROS-Mediated Apoptosis.
Epigenetic-Mitochondrial-Metabolic Crosstalk in Retinal Pigment Epithelium (RPE) Dysfunction in Age-Related Macular Degeneration (AMD).
Retinal Pigment Epithelium Cell Line ARPE-19 Exposed to M1 Microglia Releases Proinflammatory Cytokines and Reactive Oxygen Species Through MAP-Kinase Pathway.
Humanin Mitigates Aβ-Induced Retinal Pigment Epithelium Injury via AMPK-Beclin1-Dependent Mitophagy.
Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.
Marine-Derived Fucoidan Modulates Pathways Associated with Age-Related Macular Degeneration in Cellular and Zebrafish Models.
Metformin and cRGDfc-Modified Nanoparticles Loaded with Curcumin for Age-Related Macular Degeneration: In Vitro Pharmacodynamics and Molecular Mechanisms.

Antioxidants (Basel). 2026 Jun 18. pii: 765. [Epub ahead of print]15(6):

Tetrahydrocurcumin Attenuates NaIO3-Induced Retinal Oxidative Injury via Suppression of NOX2-Derived ROS-Mediated Apoptosis.

Tzu-Chun Chen, Thuy-Lan-Thi Vo, Shang-Chun Tsou, Hui-Min David Wang, Inga Wang, Chen-Ju Chuang, Hui-Wen Lin, Yuan-Yen Chang.

  Oxidative stress is a major contributor to the development of age-related macular degeneration (AMD), and excessive oxidative stress can induce retinal pigment epithelium (RPE) dysfunction, apoptosis, and retinal degeneration. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) is a major enzymatic source of reactive oxygen species (ROS); however, its mechanistic role in sodium iodate (NaIO3)-induced oxidative injury remains unclear. Tetrahydrocurcumin (THC), the major metabolite of curcumin, exhibits potent antioxidant and cytoprotective activities, but its protective effects against AMD-associated retinal degeneration have not been fully elucidated. In the present study, we investigated whether THC protects against NaIO3-induced ROS-mediated apoptosis in RPE cells through regulation of NOX2 signaling. In vitro, THC significantly attenuated NaIO3-induced cytotoxicity and prevented apoptosis by suppressing hydrogen peroxide (H2O2) production and intracellular ROS accumulation in ARPE-19 cells. THC also preserved mitochondrial membrane potential by inhibiting the Src/p47phox/NOX2 signaling pathway and subsequently attenuated mitochondria-mediated apoptotic signaling. Furthermore, THC markedly reduced the expression of apoptotic proteins, including Bax, cleaved caspase-3, and cleaved PARP, concomitantly with suppression of Ras/Raf/MEK/ERK signaling. Mechanistically, treatment with the selective NOX2 inhibitor GSK2795039 significantly attenuated NaIO3-induced ROS accumulation and mitochondrial depolarization, while co-treatment with THC further enhanced these protective effects. In vivo, THC ameliorated NaIO3-induced retinal structural abnormalities by preserving the outer nuclear layer (ONL), reducing caspase-3 expression, and improving pupillary light responses in mice. Collectively, these findings demonstrate that THC protects against NaIO3-induced retinal degeneration through suppressing NOX2-dependent oxidative stress and downstream Ras/Raf/MEK/ERK-mediated apoptotic signaling, highlighting its potential as a therapeutic candidate for AMD and other oxidative stress-related retinal disorders.

Keywords:  NOX2 and MEK/ERK signaling pathway; NaIO3; age-related macular degeneration (AMD); apoptosis; tetrahydrocurcumin (THC)

DOI:  https://doi.org/10.3390/antiox15060765
Antioxidants (Basel). 2026 Jun 04. pii: 713. [Epub ahead of print]15(6):

Epigenetic-Mitochondrial-Metabolic Crosstalk in Retinal Pigment Epithelium (RPE) Dysfunction in Age-Related Macular Degeneration (AMD).

Yijing Yang, Ying Deng, Xiang Li, Pai Zhou, Qinghua Peng, J Arjuna Ratnayaka.

  Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older adults and is characterized by progressive dysfunction of the retinal pigment epithelium (RPE). Although genetic susceptibility and environmental exposure both contribute to disease risk, the mechanisms through which chronic metabolic and oxidative stress are integrated into sustained RPE dysfunction remain incompletely understood. Increasing evidence from human AMD donor tissue and experimental RPE models indicates that epigenetic regulation operates at the interface between mitochondrial dysfunction, redox imbalance, and transcriptional remodeling. This review synthesizes current findings on DNA methylation, chromatin accessibility, histone modification, and RNA-based regulation in AMD, with emphasis on their metabolic and mitochondrial context. Studies in human AMD-RPE demonstrate that epigenetic alterations are generally selective rather than global and frequently involve pathways related to mitochondrial maintenance, lipid metabolism, oxidative stress responses, and cellular homeostasis. Mechanistically, mitochondrial dysfunction and reactive oxygen species (ROS) may influence epigenetic regulation through altered Nicotinamide adenine dinucleotide (NAD+) availability, acetyl-CoA metabolism, redox-sensitive chromatin regulation, and modulation of DNA methyltransferase and histone deacetylase activity. Redox-sensitive pathways, including antioxidant signaling, further connect mitochondrial stress to adaptive or maladaptive transcriptional responses in the RPE. Importantly, while several interactions discussed are supported by findings in human AMD tissue, other components of the proposed epigenetic-mitochondrial-redox framework remain inferential or model-based and require further validation. Rather than acting as isolated disease triggers, epigenetic changes are more likely to function as stress-responsive regulatory layers that stabilize transcriptional states over time in a long-lived post-mitotic tissue. We further discuss unresolved questions regarding causality, reversibility, therapeutic feasibility, and stage-specific intervention strategies. Collectively, this framework positions the epigenetic-mitochondrial-redox axis as a unifying model for understanding RPE vulnerability and AMD progression.

Keywords:  age-related macular degeneration; chromatin remodeling; epigenetic regulation; mitochondrial dysfunction; redox signaling; retinal pigment epithelium

DOI:  https://doi.org/10.3390/antiox15060713
Brain Sci. 2026 May 28. pii: 568. [Epub ahead of print]16(6):

Retinal Pigment Epithelium Cell Line ARPE-19 Exposed to M1 Microglia Releases Proinflammatory Cytokines and Reactive Oxygen Species Through MAP-Kinase Pathway.

Michela Pizzoferrato, Benedetto Falsini, Giuseppe Tringali, Pierluigi Navarra, Lucia Lisi.

  Background: The retinal pigment epithelium (RPE) plays a pivotal role in the visual process by maintaining the blood-retina barrier, protecting the retina from oxidative stress, and regulating immune responses. Consequently, dysfunction or degeneration of the RPE is implicated in a broad spectrum of retinal disorders that lead to progressive and irreversible vision loss. In this context, inflammation of the RPE has emerged as a critical factor in the pathogenesis of retinal degenerative diseases, underscoring its dual role as both a target and mediator of retinal inflammatory processes within the retina. Objectives: This study aims to preliminarily investigate, mainly by assessment of proinflammatory cytokine gene expression and immunoblotting, the molecular mechanisms underlying RPE inflammation induced by interactions between the RPE and microglia of the central nervous system. Methods/Results: Using in vitro models of human RPE cells, the ARPE 19 cell line was exposed to conditioned media from microglia (CHME-5 cell line) under basal and proinflammatory conditions. We observed increased activation of the MAPK signaling pathway, (evidenced by a 4-fold increase in the phosphorylation ratio of MEK and ERK) alongside elevated expression of proinflammatory cytokines, assessed by RT-PCR and immunoblotting, and a 2-fold increase in reactive oxygen species levels in RPE cells, evaluated by colorimetric assays, after exposure with conditioned media. Specifically, IL-1β and IL-8 levels increased more than 40-fold, while IL-6 expression showed a 4-fold increase compared to controls. Conclusions: These findings emphasize the central role of the RPE in retinal inflammation and suggest potential therapeutic targets to modulate immune responses and preserve retinal function.

Keywords:  MAPK signaling pathway; microglia; oxidative stress; retinal pigment epithelium (RPE)

DOI:  https://doi.org/10.3390/brainsci16060568
Aging Cell. 2026 Jul;25(7): e70601

Humanin Mitigates Aβ-Induced Retinal Pigment Epithelium Injury via AMPK-Beclin1-Dependent Mitophagy.

Ha Young Jang, Suyeon Choi, Soo-Jin Kim, Sooyun Kim, Dong Hyun Jo, Tae Geol Lee, Kyu-Sang Park, Jeong Hun Kim.

  Amyloid beta (Aβ), a key component of drusen in age-related macular degeneration (AMD), induces oxidative stress, mitochondrial dysfunction, and degeneration in the retinal pigment epithelium (RPE), contributing to progressive vision loss in the elderly. We investigated the protective role of Humanin (HN), a mitochondria-derived peptide with known neuroprotective effects in Aβ-related neurodegenerative diseases, in retinal pathology induced by subretinal injection of FITC-labeled Aβ. HN enhanced the clearance of Aβ-accumulated mitochondria in the RPE while preserving retinal function and RPE barrier integrity. In ARPE-19 cells, HN activated AMP-activated protein kinase (AMPK), leading to phosphorylation of ULK1 and Beclin1, which promoted the interaction between Beclin1 and Parkin and their translocation to mitochondria. This process facilitated the removal of Aβ-accumulated mitochondria in the RPE. Our results demonstrate that targeting mitophagy in the RPE with HN may offer a promising therapeutic strategy for AMD.

Keywords:  age‐related macular degeneration; amyloid beta; humanin; mitochondrial dysfunction; retinal pigment epithelium

DOI:  https://doi.org/10.1111/acel.70601
Curr Issues Mol Biol. 2026 Jun 11. pii: 612. [Epub ahead of print]48(6):

Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.

Feliciana Menna, Stefano Lupo, Laura De Luca, Antonio Baldascino, Enzo Maria Vingolo, Alessandro Meduri.

  Mitochondrial dysfunction and oxidative stress are increasingly recognized as key contributors to the development and progression of retinal degenerative diseases, including age-related macular degeneration and inherited retinal dystrophies. Growing evidence suggests that alterations in mitochondrial function, excessive production of reactive oxygen species, defective mitophagy, and chronic inflammatory responses are closely interconnected processes that contribute to retinal cell damage and degeneration. This review provides an overview of the current understanding of the molecular mechanisms linking mitochondrial dysfunction to retinal degeneration, with particular emphasis on the impact of oxidative stress, mitochondrial quality-control pathways, and inflammatory signaling. Available evidence indicates that mitochondrial DNA damage, impaired bioenergetics, and dysregulated mitochondrial dynamics play a crucial role in the degeneration of photoreceptors and retinal pigment epithelium cells. In turn, oxidative stress further exacerbates mitochondrial impairment, creating a self-sustaining cycle that promotes disease progression. Recent advances have also highlighted the therapeutic potential of targeting mitochondrial pathways. Although several mitochondria-directed strategies have shown encouraging results in experimental models, their translation into clinical practice remains at an early stage. Overall, the available data identify mitochondria as a promising therapeutic target and support the development of precision medicine approaches aimed at preserving retinal function and slowing disease progression in patients with retinal degenerative disorders.

Keywords:  biomarkers; mitochondrial dysfunction; mitochondrial therapy; mitophagy; oxidative stress; reactive oxygen species; retinal degeneration; retinal pigment epithelium

DOI:  https://doi.org/10.3390/cimb48060612
Mar Drugs. 2026 Jun 16. pii: 216. [Epub ahead of print]24(6):

Marine-Derived Fucoidan Modulates Pathways Associated with Age-Related Macular Degeneration in Cellular and Zebrafish Models.

Haqdil Hakeem Shad, Philipp Dörschmann, Samira Laura Hautmann, Johann Roider, Alexa Klettner.

  Fucoidan, a sulfated polysaccharide, is known for its beneficial bioactive effects, for example antioxidant, anti-inflammatory, and vascular modulatory effects. Such a bioactive compound may also be useful for treating neurodegenerative diseases like age-related macular degeneration (AMD). Our research focuses on AMD-related pathomechanisms using primary porcine retinal pigment epithelium (RPE) cells in vitro and zebrafish (Danio rerio) models in vivo. We tested the bioactivity of a commercially available fucoidan (FVs) from bladderwrack with regard to pathomechanisms of AMD. We performed multiplex assays, RT-qPCR and fluorescence-based assays for the formation of nitric oxide (DAF-FM assay) and reactive oxygen species (DCF-DA assay) to analyze angiogenesis-related chemokines and pro-inflammatory cytokines as well as protection against oxidative stress and inflammatory insult. Our results showed that FVs significantly reduced the secretion of pro-angiogenic vascular endothelial growth factor A (VEGF-A) and follistatin as well as the pro-inflammatory cytokines interleukin 8 (IL-8) after lipopolysaccharide (LPS) and polyinosinic/polycytidylic acid (PIC) induction. Interleukin 6 (IL-6) was also reduced in the supernatant of the RPE cells. Additionally, in zebrafish, fucoidan decreased the production of NO and ROS. Gene expression of zebrafish embryos revealed anti-inflammatory effects by suppressing pro-inflammatory genes and significantly downregulating, e.g., interleukin 1 beta (IL-1β). These findings indicate modulation of oxidative stress, inflammatory responses, and VEGF secretion of the used FVs. This study demonstrates that fucoidan possesses AMD-relevant bioactivities in vitro and in vivo, suggesting fucoidan warrants further investigation in AMD-related research and related pathological mechanisms.

Keywords:  age-related macular degeneration (AMD); fucoidan; gene expression; innate immunity; neurodegenerative diseases; nitric oxide (NO); polysaccharide; porcine retinal pigment epithelium (RPE); reactive oxygen species (ROS); vascular endothelial growth factor A (VEGF-A); zebrafish (Danio rerio)

DOI:  https://doi.org/10.3390/md24060216
Pharmaceutics. 2026 Jun 22. pii: 761. [Epub ahead of print]18(6):

Metformin and cRGDfc-Modified Nanoparticles Loaded with Curcumin for Age-Related Macular Degeneration: In Vitro Pharmacodynamics and Molecular Mechanisms.

Juan Liu, Ziheng Wang, Yuchang Yang, Lisha Yi, Shiman Li, Jingyi Gao, Jia Zhou, Nannan Cheng, Xingbin Yin, Xiaoxv Dong, Jian Ni, Changhai Qu.

  Objectives: This study aimed to develop curcumin nanoparticles (Cur@PCL-PEG-MF/cRGDfc) with retinal-targeting capability and to evaluate their biological effects and pharmacological mechanisms in vitro. Methods: After synthesis of the carrier framework, metformin (MF) and cRGDfc were conjugated to the carrier material using the carbodiimide method and Michael addition reaction, respectively. Subsequently, self-assembled nanoparticles were formed from the carrier and curcumin under specific conditions. The materials were characterized by spectroscopy, chromatography, elemental analysis, energy-dispersive spectroscopy and X-ray diffraction. The efficacy of the formulation was evaluated in two cell lines, ARPE-19 and HUVEC-T1. In addition, the pharmacological mechanism was explored using transcriptome sequencing as a complementary approach. Key Findings: Self-assembled nanoparticles were successfully prepared by combining the two modified carrier materials, PCL-PEG-MF and PCL-PEG-cRGDfc, with curcumin. The nanoparticles exhibited an encapsulation efficiency of 78.09%, a particle size of 162.33 nm, and a zeta potential of -23.28 mV and displayed a spherical morphology. They showed sustained release in simulated physiological conditions and stronger affinity for ARPE-19 cells under oxidative stress. Nearly 100% of the nanoparticles were internalized by the cells, which was accompanied by reduced ROS and LDH release and decreased DNA fragmentation. In addition, the nanoparticles inhibited neovascularization by reducing VEGF-A release, thereby potentially protecting the retina in macular degeneration and reducing choroidal hemorrhage. Further analyses showed that curcumin and its nanoformulations significantly reduced the expression of inflammatory factors such as IL-1β and IL-18, lowered the protein levels of Caspase-1, GSDMD-N, and NLRP3, and increased AMPK levels. Conclusions: Using PCL-PEG as the carrier framework, MF and cRGDfc were conjugated to construct a curcumin-loaded nanoparticle with retinal-targeting capability. This nanoparticle, characterized by a small particle size, sustained release, and targeted delivery to retinal pigment epithelium (RPE) cells under oxidative stress, alleviated oxidative stress-induced damage. Its therapeutic effect may be mediated, at least in part, by interference with the AMPK/mTOR pathway and activation of the NLRP3/Caspase-1/GSDMD pathway.

Keywords:  age-related macular degeneration (AMD); curcumin; molecular mechanism; nanoparticle; pharmacodynamics

DOI:  https://doi.org/10.3390/pharmaceutics18060761