bims-mideyd 2026-05-17 papers

Eur J Pharmacol. 2026 May 13. pii: S0014-2999(26)00457-7. [Epub ahead of print] 178975

Characterization of mitochondrial dysfunction induced by BAX trigger site activator 1 in the ARPE-19 retinal pigment epithelial cell model.

Toshihide Kashihara, Yuka Akiyama, Akane Morita, Saori Deguchi, Ryosuke Odaka, Tsutomu Nakahara.

Mitochondrial dysfunction in the retinal pigment epithelium (RPE) is a key pathological feature of age-related macular degeneration (AMD). However, mechanistically defined experimental models that recapitulate stress-mediated mitochondrial injury remain limited. Bcl-2-associated X (BAX), a key pro-apoptotic effector, serves as a critical upstream regulator of mitochondrial outer membrane permeabilization. In this study, we systematically characterized mitochondrial dysfunction induced by BAX trigger site activator 1 (BTSA1), a selective small-molecule BAX activator, in ARPE-19 cells. Treatment with BTSA1 (3-60 μM) for 24 and 48 h induced a concentration- and time-dependent reduction in cell viability, accompanied by caspase-3 activation. Mitochondrial membrane potential, assessed via tetramethylrhodamine ethyl ester staining, was markedly reduced in a BAX-dependent manner and associated with increased reactive oxygen species production following prolonged exposure or at high concentrations. BTSA1 profoundly altered mitochondrial dynamics by promoting DRP1-mediated fission while suppressing fusion through MFN2 downregulation and stress-associated OPA1 processing, resulting in pronounced mitochondrial fragmentation. Furthermore, BAX activation elicited a biphasic response in mitochondrial quality control pathways: mild stress induced impaired autophagic flux and compensatory mitochondrial biogenesis, whereas severe stress triggered mitophagy accompanied by failure of biogenic compensation. These coordinated alterations closely mirror mitochondrial pathologies observed in the degenerating RPE in AMD. Collectively, our findings demonstrate that BAX activation by BTSA1 is sufficient to induce a comprehensive cascade of mitochondrial dysfunction. This system represents a mechanistically defined experimental model for dissecting BAX-mediated mitochondrial pathology and evaluating therapeutic strategies to preserve mitochondrial integrity in AMD.

Keywords: Age-related macular degeneration (AMD); BAX activation; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial quality control; Retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1016/j.ejphar.2026.178975

Exp Eye Res. 2026 May 12. pii: S0014-4835(26)00220-4. [Epub ahead of print] 111064

Metabolic Reprogramming and Mitochondrial Dynamics: Novel Therapeutic Perspectives for Age-Related Macular Degeneration.

Zhuopeng Hu, Hang Qi, Xinyu Dong, Ye Tian, Minying Sun, Xiaoyan Jia, Huimei Yu.

Age-related macular degeneration (AMD) represents the leading cause of irreversible vision loss in the elderly, affecting over 200 million individuals worldwide. Despite recent advances, therapeutic options remain severely limited, particularly for dry AMD characterized by progressive geographic atrophy. Emerging evidence implicates mitochondrial dysfunction and metabolic reprogramming of retinal pigment epithelium (RPE) cells as central pathogenic drivers. Under pathological conditions, RPE cells exhibit profound bioenergetic collapse marked by declining oxidative phosphorylation, compensatory glycolytic activation, and aberrant tricarboxylic acid cycle intermediate accumulation. This metabolic catastrophe is structurally underpinned by dysregulated mitochondrial dynamics. The resultant accumulation of fragmented, dysfunctional mitochondria perpetuates reactive oxygen species overproduction and mitochondrial DNA damage, establishing a self-amplifying vicious cycle driving RPE degeneration. Mechanistically, this involves dysregulation of the AMPK/mTOR energy-sensing axis, SIRT1/PGC-1α transcriptional control, and Nrf2/ARE antioxidant defenses. Multi-omics profiling reveals distinct metabolic signatures. These discoveries have catalyzed mechanism-based interventions. However, translational applications still face many challenges, and the combination of single-cell multi omics and multimodal therapies is expected to play a role.in restoring mitochondrial homeostasis and preserving vision in aging population in the future.

Keywords: Age-related macular degeneration; Metabolic reprogramming; Mitochondrial dynamics; Mitophagy; Oxidative stress; Precision therapy; Retinal pigment epithelium

DOI: https://doi.org/10.1016/j.exer.2026.111064

J Clin Med. 2026 Apr 24. pii: 3254. [Epub ahead of print]15(9):

Targeting Neuroinflammation and Oxidative Stress to Slow Neurodegeneration in the Visual System.

Nara Shakaki, Minzhong Yu.

PURPOSE: Neuroinflammation and oxidative stress are increasingly recognized as central, interconnected drivers of neurodegeneration in the visual system. This review examines the pathogenic mechanisms shared across glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and Alzheimer's disease (AD), and evaluates the therapeutic rationale for targeting both pathways simultaneously.
METHODS: A narrative review of peer-reviewed literature was conducted using PubMed. Searches combined the following MeSH terms: neuroinflammation, oxidative stress, retinal neurodegeneration, microglia, Müller glia, mitochondrial dysfunction, glaucoma, age-related macular degeneration, diabetic retinopathy, and Alzheimer's disease. Priority was given to original research, systematic reviews, and high-impact publications from 2000 through 2025. However, seminal foundational works were included regardless of publication date. Studies were selected based on relevance to glial activation, mitochondrial dysfunction, reactive oxygen and nitrogen species, and disease-specific neuronal outcomes.
RESULTS: Across all four diseases, persistent microglial and Müller glial activation, mitochondrial electron transport chain dysfunction, and excess reactive oxygen species (ROS) and reactive nitrogen species (RNS) production form a self-amplifying feed-forward loop that accelerates neuronal injury. In glaucoma, these mechanisms drive intraocular pressure-independent retinal ganglion cell loss. In AMD and DR, lipid dysregulation, complement activation, and chronic hyperglycemia sustain oxidative-inflammatory injury to the retinal pigment epithelium, photoreceptors, and neurovasculature. In AD, retinal amyloid deposition and oxidative stress mirror cortical pathology, positioning the retina as a noninvasive biomarker site.
CONCLUSIONS: Neuroinflammation and oxidative stress constitute unifying upstream mechanisms across major vision-threatening neurodegenerative diseases. Combination therapeutic strategies that simultaneously modulate glial activation and restore redox homeostasis may offer superior neuroprotective efficacy compared to approaches targeting isolated downstream mediators.

Keywords: Alzheimer’s disease; age-related macular degeneration; diabetic retinopathy; glaucoma; neuroinflammation; oxidative stress

DOI: https://doi.org/10.3390/jcm15093254

Exp Eye Res. 2026 May 13. pii: S0014-4835(26)00224-1. [Epub ahead of print] 111068

A Human Amelotin Transgenic Mouse Model with Calcified Deposits Similar to Those in Dry Age-related Macular Degeneration.

Dinusha Rajapakse, Jianguo Fan, Dannika Daily, Lijin Dong, Katherine Peterson, Robert Fariss, Graeme Wistow.

Amelotin (AMTN), a protein involved in enamel formation, is induced in retinal pigment epithelial (RPE) in patients with dry age-related macular degeneration (AMD) and is associated with calcification in drusen. To examine the effects of constitutive expression of human AMTN in RPE we created a transgenic (TG) mouse model that expresses human AMTN specifically in the RPE using the regulatory components of the mouse Rpe65 gene. This led to several AMD-like abnormalities in RPE but did not produce calcified depositions. Reasoning that other aspects of cell stress or damage may be needed for calcification we tested moderate laser injury of the retina in young TG and WT mice. TG mice, but not WT, developed AMTN-dependent deposits containing AMTN, cholesterol, and calcium phosphate/HAP in the laser lesions, reminiscent of deposits seen in dry AMD drusen. While laser lesions in WT mice healed normally, those in TG mice progressed, obliterating adjacent photoreceptors and recruiting microglia. This shows that chronic expression of AMTN can induce pathologies in RPE and that when coupled with injury can form structures similar to calcified drusen. These deposits are associated with increased retinal damage and inflammation. The model presents a system to test possible therapeutic effects of inhibition or suppression of AMTN in RPE in vivo.

Keywords: Age-related macular degeneration; Amelotin; Calcium phosphate; Disease Models; Drusen; Hydroxyapatite; Mouse models

DOI: https://doi.org/10.1016/j.exer.2026.111068

bioRxiv. 2026 Mar 01. pii: 2026.02.26.708319. [Epub ahead of print]

Single Cell Transcriptomics and Surface Protein Expression Reveal Distinct Cellular and Molecular Phenotypes in Human RPESC-RPE and PSC-RPE.

Swapna Nandakumar, Farhad Farjood, Taylor Bertucci, Steven Lotz, Skanda Sai, Yue Wang, Jade A Kozak, Brigitte L Arduini, Jeffrey H Stern, Nathan C Boles, Sally Temple.

Current retinal pigment epithelium (RPE) cell replacement strategies in trials for age-related macular degeneration (AMD) are based on either pluripotent stem cell (PSC) or adult RPE stem cell (RPESC) sources. We used Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) to simultaneously assess single-cell transcriptomic and surface protein information, comparing these two RPE sources. Both RPESC-RPE and PSC-RPE expressed key RPE markers and exhibited cellular heterogeneity. However, RPESC-RPE had higher expression of genes related to mature retinal functions, whereas PSC-RPE had greater expression of genes involved in stem cell development and differentiation. We identified two surface proteins that distinguished the cell types. The "don't eat me" signal, CD24, was detected robustly on adult RPESC-RPE cells, while CD57 was detected on most PSC-RPE cells. The differences in gene and surface protein expression suggest that the two RPE sources differ in functional, adhesion, and immunomodulatory properties, which may impact transplantation outcomes.

DOI: https://doi.org/10.64898/2026.02.26.708319