bims-mideyd 2026-03-29 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2026–03–29
ten papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa

Mapping the Hypoxic Fitness Landscape of Retinal Pigment Epithelial Cells.
Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.
Mechanisms of Programmed Cell Death in Sodium Iodate-Driven Retinal Degeneration and the Role of DJ-1.
LDHA protects vascular endothelial cells from oxidative stress‑induced mitochondrial damage via HIF‑1α activation and glycolytic reprogramming.
Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
Hyperosmolar stress induces monocyte chemoattractant protein 1 expression in retinal pigmented epithelial arising retinal pigmented epithelial 19 cells.
All-Trans Retinoic Acid Modulates MicroRNA-129-5p/Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth Factor Signaling and Suppresses Ets-1 in Retinal Pigment Epithelial ARPE-19 Cells.
Visible Light Optical Coherence Tomography Reveals Aging at the Retinal Pigment Epithelium-Bruch's Membrane Interface.
Inner-retinal changes in AMD: Evidence, mechanisms, and future perspectives.
Spatial transcriptomic profiling identifies lacrimal-gland-epithelial cell-driven mechanisms underlying autoimmunity in Sjögren's disease.

Int J Mol Sci. 2026 Mar 21. pii: 2857. [Epub ahead of print]27(6):

Mapping the Hypoxic Fitness Landscape of Retinal Pigment Epithelial Cells.

Ozlem Calbay, Chen-Lin Hsieh, Charles Lu, Sujana Ghosh, Vinny Vijaykumar, Isabella Watts, Harry Sweigard, Jarel Gandhi, Anneke I den Hollander.

  Chronic hypoxia is a hallmark of aging and retinal diseases such as age-related macular degeneration (AMD), yet the molecular mechanisms that enable retinal pigment epithelium (RPE) cells to survive under sustained low-oxygen conditions remain poorly understood. To address this, we conducted transcriptomic profiling and a genome-wide CRISPR-Cas9 loss-of-function screen in ARPE-19 cells exposed to chronic hypoxia (1% and 5% O2), mimicking the retinal disease environment. The CRISPR screen identified genes whose loss compromises RPE viability or fitness under hypoxia, while transcriptomic profiling revealed oxygen-dependent shifts in key functional modules. These findings converged on pathways related to mitochondrial function, extracellular matrix remodeling, vascular signaling, and cell cycle regulation, identifying unique functional nodes specific to RPE cells. These core processes are also implicated in retinal diseases, such as AMD. Together, these complementary approaches provide an integrated view of the molecular networks driving RPE adaptation to hypoxic stress and highlight novel gene candidates that may serve as therapeutic targets in retinal disease.

Keywords:  AMD; CRISPR/Cas9; RPE; age-related macular degeneration; cell fitness; hypoxia; low oxygen; retinal pigment epithelium

DOI:  https://doi.org/10.3390/ijms27062857
J Biol Chem. 2026 Mar 23. pii: S0021-9258(26)00267-X. [Epub ahead of print] 111397

Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.

Hiroto Yasuda, Shinsuke Nakamura, Aimi Shirakawa, Yoshiki Kuse, Kazutoshi Mori, Masamitsu Shimazawa.

  Retinal pigment epithelium (RPE) plays a crucial role in maintaining visual function by phagocytosing photoreceptor outer segments (POS). Age-related decline in RPE phagocytic activity has been linked to the development of degenerative retinal diseases, including age-related macular degeneration (AMD). However, the underlying mechanisms of RPE phagocytic dysfunction remain poorly understood. In this study, we examined age-related induction of endoplasmic reticulum (ER) stress in RPE cells and its association with POS phagocytosis using tissues from middle-aged mice and cultured RPE cells. In the RPE-choroid complex of 12-month-old mice, ER stress marker proteins were significantly upregulated compared to younger mice. Notably, this increase was absent in the neural retina at the same age. In cultured RPE cells, pharmacological induction of ER stress by tunicamycin (Tm) significantly reduced both phagocytic activity and lysosomal function. Treatment with sodium 4-phenylbutyrate, a chemical chaperone, and transfection with chaperone protein-inducible plasmids alleviated the ER stress-induced phagocytic dysfunction in RPE cells. In the lysates of ER stress-induced RPE cells, the extracellular domain of Mer tyrosine kinase receptor (MERTK) and phosphorylation of focal adhesion kinase were significantly decreased. Mechanistically, ER stress promoted the maturation of a disintegrin and metalloprotease 17 (ADAM17) through Ca2+-dependent activation of the Furin protease, leading to MERTK shedding. Furthermore, ADAM17 knockdown attenuated the Tm-induced impairment of POS internalization. Collectively, our findings suggest that ER stress impairs RPE phagocytosis through an integrated mechanism and may contribute to the pathogenesis of AMD.

Keywords:  ADAM; aging; calcium intracellular release; endoplasmic reticulum stress (ER stress); eye; phagocytosis; retina

DOI:  https://doi.org/10.1016/j.jbc.2026.111397
Int J Mol Sci. 2026 Mar 10. pii: 2541. [Epub ahead of print]27(6):

Mechanisms of Programmed Cell Death in Sodium Iodate-Driven Retinal Degeneration and the Role of DJ-1.

Mala Upadhyay, Caroline Milliner, Vera L Bonilha.

  Oxidative stress-induced RPE cell death is a major cause of AMD pathogenesis. However, the exact modes of oxidative stress-driven retinal death remain elusive. To address this knowledge gap, we investigated the role of DJ-1, an antioxidant protein we previously characterized in the retina, in cell death regulation. Specifically, we analyzed cell death pathways in the retinas of DJ-1 knockout (KO) mice, with or without sodium iodate (NaIO3) injection. We quantified MAPK signaling protein activation by Western blot. The distribution of the cell death executioners, activated caspase 3, and pMLKL, was investigated. The effects of caspase and necroptosis inhibitors in mice previously injected with NaIO3 were determined. Significant increases in JNK1/2 activation and FOXO1 levels were detected in RPE lysates when DJ-1 KO mice were injected with 10 mg/kg NaIO3. The immunoreactivity of active caspase-3 and pMLKL was stronger in the retinas of DJ-1 KO compared with C57BL mice. These immunoreactivities further increased in the degenerating outer retina post NaIO3 injection and were stronger in the retina of DJ-1 KO compared with C57BL mice at both doses of NaIO3. ZVAD treatment rescued retinal degeneration to varying degrees in DJ-1 KO mice. However, necrostatin (Nec-1) alleviated retinal degeneration in both DJ-1 KO and C57BL mice, suggesting that apoptosis is a major cell death modality in the absence of DJ-1. Overall, oxidative stress-induced RPE and retinal cell death involve activation of both apoptosis and necroptosis in the absence of DJ-1.

Keywords:  DJ-1; RPE; apoptosis; necroptosis; retina; sodium iodate

DOI:  https://doi.org/10.3390/ijms27062541
Mol Med Rep. 2026 May;pii: 141. [Epub ahead of print]33(5):

LDHA protects vascular endothelial cells from oxidative stress‑induced mitochondrial damage via HIF‑1α activation and glycolytic reprogramming.

Beibei Dai, Lili Yang, Yu Zhang, Aiyong Yu.

  Oxidative stress‑induced damage contributes to endothelial dysfunction, a key feature in the pathogenesis of cerebral aneurysms (CAs). Lactate dehydrogenase A (LDHA) serves a crucial role in regulating metabolic adaptation under stress. The present study aimed to explore the protective effects of LDHA overexpression on vascular endothelial cells (VECs) under oxidative stress induced by hydrogen peroxide (H2O2). VECs were exposed to 0.5 mM H2O2 in an oxygen‑glucose deprivation/reperfusion (OGD/R) model to induce oxidative stress, mimicking conditions relevant to CA. LDHA overexpression was achieved using a plasmid vector. Subsequently, western blotting, flow cytometry, reverse transcription‑quantitative polymerase chain reaction, transmission electron microscopy and JC‑1 staining were used to assess apoptosis, mitochondrial function, glycolysis and oxidative stress markers. Extracellular acidification rate was measured to evaluate glycolytic activity. The results revealed that LDHA overexpression reduced oxidative stress‑induced apoptosis and mitochondrial damage in VECs, as evidenced by decreased caspase activation (caspase‑3, caspase‑9), preserved mitochondrial structure and improved mitochondrial membrane potential. Additionally, LDHA overexpression mitigated reactive oxygen species production and activated hypoxia‑inducible factor 1α (HIF‑1α). It also increased the expression of glycolytic genes (hexokinase 2, phosphoglucomutase 5 and pyruvate kinase M) and upregulated the lactate transporter monocarboxylate transporter 4, while decreasing succinate levels. Furthermore, LDHA overexpression enhanced NADPH levels and glucose‑6‑phosphate dehydrogenase activity, indicating the activation of the pentose phosphate pathway to maintain redox balance. In conclusion, LDHA may protect VECs from mitochondrial dysfunction and oxidative damage in the context of CA by enhancing glycolytic metabolism and HIF‑1α signaling. LDHA could therefore serve as a possible therapeutic target for the treatment and prevention of CAs.

Keywords:  cerebral aneurysms; glycolytic reprogramming; hypoxia‑inducible factor 1α; lactate dehydrogenase A; mitochondrial damage

DOI:  https://doi.org/10.3892/mmr.2026.13851
Biomolecules. 2026 03 16. pii: 445. [Epub ahead of print]16(3):

Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.

Snježana Kaštelan, Antonela Gverović Antunica, Suzana Konjevoda, Zora Tomić, Ana Sarić, Marjan Kulaš, Lorena Kulaš, Emina Kujundžić Begović, Samir Čanović, Petra Kovačević, Mira Ivanković.

  Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification.

Keywords:  mitochondria-targeted intervention; mitochondrial quality control; mitochondrial reactive oxygen species (mtROS); mitophagy; precision medicine; redox signalling; retinal ganglion cells; retinal neurodegeneration; reverse electron transport

DOI:  https://doi.org/10.3390/biom16030445
Mol Vis. 2025 ;31 380-394

Hyperosmolar stress induces monocyte chemoattractant protein 1 expression in retinal pigmented epithelial arising retinal pigmented epithelial 19 cells.

Moncef Ould Hamou, Maureen Masset, Célia Weber, Lisa Scifo, Sarah Libert, Angélic Bryla, Françoise Gregoire, Valérie Delforge, Nargis Bolaky, Azine Datlibagi, Jean-Yves Springael, Jason Perret, François Willermain, Christine Delporte.

Purpose: Diabetes is a chronic inflammatory disease that may damage the blood-retinal barrier, leading to diabetic retinopathy (DR). Blood-retinal barrier rupture may subject the retinal pigmented epithelial cells to a hyperosmolar stress (HOS), activating the transcription factor nuclear factor of activated T cells 5 (NFAT5). In addition, inflammatory cytokines, such as monocyte chemoattractant protein 1 (MCP-1/CCL2), play a crucial role in DR. The aims of our study were to determine whether HOS induces MCP-1 levels in arising retinal pigmented epithelial 19 (ARPE-19) cells and to decipher the responsible intracellular cascade involved in such stimulation.
Methods: ARPE-19 cells or ARPE-19 cells transfected with dominant negative NFAT5 plasmid or NFAT5 short hairpin RNA plasmids were preincubated or not for 1 h in the absence or presence of a protein kinase or transcription factor inhibitor and then incubated for 8 h with iso-osmolar or hyperosmolar medium in the absence or presence of inhibitor. NFAT5 reporter gene activity was quantified by luminescence. MCP-1 messenger RNA (mRNA) and protein levels were determined by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Biologically active MCP-1 was assessed by a calcium mobilization assay performed using Chinese hamster ovary cells expressing or not the MCP-1 receptor and apoaequorin.
Results: In response to HOS, ARPE-19 cells showed a significant increase in MCP-1 mRNA levels independent of NFAT5 activation. Moreover, the MCP-1 protein secreted by ARPE-19 in response to HOS is biologically active. The use of various inhibitors of protein kinase and transcription factors suggest that the HOS-induced increase in MCP-1 mRNA levels is dependent on a protein kinase C (PKC) and/or a MEK1/2-p38 pathway activating p53, as well as a PKC-p38-PI3K-PDK1-AKT activating hypoxia-inducible factor 1 alpha (HIF1α).
Conclusion: HOS increases the expression of MCP-1 mRNA and protein levels in ARPE-19 cells, and the secreted MCP-1 is biologically active. The HOS-induced increase of MCP-1 mRNA appears to be independent of NFAT5 activation. Despite the activation of NFAT5 upon HOS and the presence of NFAT5 binding sites in the MCP-1 gene promoter, activated NFAT5 may not be sufficient to induce MCP-1 gene transactivation in response to HOS in ARPE-19 cells. The intracellular cascade involved in the HOS-induced increase of MCP-1 mRNA in ARPE-19 cells may consist of a PKC-p38-PI3K-PDK1-AKT-HIF1α axis and/or a MEK1/2-p38-p53 axis.
J Ocul Pharmacol Ther. 2026 Mar 23. 10807683261434410

All-Trans Retinoic Acid Modulates MicroRNA-129-5p/Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth Factor Signaling and Suppresses Ets-1 in Retinal Pigment Epithelial ARPE-19 Cells.

Yo-Chen Chang, Yuan-Chieh Yang, Po-Han Chen, Wen-Chuan Wu, Ying-Hsien Kao.

   PURPOSE: Proliferative vitreoretinopathy (PVR) is a vision-threatening complication of retinal detachment or ocular trauma characterized by the formation of contractile fibrotic membranes. Retinal pigment epithelium (RPE) cells are central to PVR pathogenesis, driving maladaptive wound-healing responses. This study investigated the effects of all-trans retinoic acid (ATRA) on RPE cell proliferation, vascular endothelial growth factor (VEGF) secretion, and miR-129-5p biogenesis, alongside the downstream regulation of Ets-1 and the hypoxia-inducible factor-1α (HIF-1α)/VEGF axis.
METHODS: Human ARPE-19 cells were treated with ATRA under quiescent or protein kinase C (PKC)-activated conditions. Proliferation, VEGF secretion, and miR-129-5p expression were quantified via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, enzyme-linked immunosorbent assay, and real-time quantitative PCR. Bioinformatic analysis, miR-129-5p mimic transfection, Western blotting, and protein ubiquitination assays were utilized to characterize the regulatory mechanisms.
RESULTS: ATRA exerted a dose- and time-dependent cytostatic effect on ARPE-19 cells without inducing cytotoxicity. VEGF modulation was highly context-dependent: basal secretion exhibited a biphasic response (peaking at 10-7 M), whereas PKC-stimulated secretion was significantly suppressed. Mechanistically, ATRA promoted intracellular miR-129-5p accumulation, which directly silenced the profibrotic factor Ets-1. Paradoxically, miR-129-5p mimic transfection stabilized HIF-1α protein by reducing its polyubiquitination, thereby enhancing VEGF production.
CONCLUSIONS: Our findings characterize miR-129-5p as a pivotal molecular switch orchestrating ATRA-mediated RPE modulation. By decoupling antifibrotic activity (Ets-1 suppression) from cytoprotective signaling (HIF-1α stabilization), this miR-129-5p/HIF-1α/VEGF axis balances the attenuation of pathological fibrosis with the preservation of homeostatic survival factors for retinal integrity, providing a nuanced therapeutic approach for PVR and the associated retinal disorders.

Keywords:  Ets-1; HIF-1α/VEGF signaling; all-trans retinoic acid; miR-129-5p; proliferative vitreoretinopathy

DOI:  https://doi.org/10.1177/10807683261434410
bioRxiv. 2026 Mar 20. pii: 2026.03.18.712487. [Epub ahead of print]

Visible Light Optical Coherence Tomography Reveals Aging at the Retinal Pigment Epithelium-Bruch's Membrane Interface.

Ruoyu Meng, Rachel C Kenney, Moning Pan, Alok K Gupta, Yasha S Modi, Pooja Chauhan, Christine A Curcio, Vivek J Srinivasan.

Landmark histological studies have shown that as the retina ages, lipids and other debris accumulate within Bruch's membrane (BM) and in spaces introduced between BM and the retinal pigment epithelium (RPE). These deposits grow with age, increasing the risk of age-related macular degeneration (AMD), the leading cause of irreversible vision loss for older adults globally. Current in vivo imaging lacks specificity to study BM and the important spaces at the RPE/BM interface in living human eyes, while histological techniques suffer from processing artifacts that distort photoreceptors. Here we employ visible light Optical Coherence Tomography (OCT), with 1 micrometer depth resolution, to quantitatively analyze these tissues in living eyes. We identify age-related changes in a human cohort without retinal pathology: thickening and loss of contrast of the hyper-reflective BM band, and thickening of the RPE together with the sub-RPE basal laminar space (RPE+sBL). Both forms of thickening were locally coupled depending on eccentricity, suggesting related biosynthetic mechanisms. A thicker BM and RPE+sBL were locally associated with anomalies in the overlying photoreceptors. Thus, sub-clinical changes in aging eyes detected by visible light OCT resemble early versions of deposits found in AMD. Visible light OCT depicts the relationship between RPE+sBL, BM, and photoreceptors in aging, holding promise to precisely and non-invasively grade ocular phenotypes ranging from normal aging to early AMD.
Significance Statement: As humans age, lipids and other debris deposit in Bruch's membrane (BM) of the human eye (1) and spaces introduced between the retinal pigment epithelium (RPE) and BM. These deposition processes are linked to the eventual development of age-related macular degeneration (AMD), the leading blinding disease amongst older adults. Here we investigate these deposits with visible light OCT imaging in living human subjects without overt retinal pathology. Whereas early RPE/BM deposits were previously assessed only in donor eyes postmortem via preparations that distort photoreceptors, our results shed light on these AMD precursors and overlying photoreceptor changes in living human eyes.

DOI: https://doi.org/10.64898/2026.03.18.712487
Prog Retin Eye Res. 2026 Mar 21. pii: S1350-9462(26)00029-7. [Epub ahead of print]112 101463

Inner-retinal changes in AMD: Evidence, mechanisms, and future perspectives.

Matt Trinh, Michael Kalloniatis, Bryan William Jones, Glenn C Yiu, Enrico Borrelli, Lisa Nivison-Smith.

  Age-related macular degeneration (AMD) has traditionally been regarded as a disorder of the outer-retina and choroid, characterised by drusen accumulation, retinal pigment epithelium (RPE) dysfunction, and photoreceptor degeneration. However, increasing evidence of inner-retinal involvement across the AMD spectrum, with structural and functional compromise evident from the early stages of disease, challenges this paradigm. Advances in spatially optimised optical coherence tomography (OCT), OCT angiography (OCTA), and high-resolution histology have revealed neuronal, vascular, and glial alterations within the inner-retina that reshape our understanding of AMD pathogenesis. This review synthesises clinical and experimental evidence on inner-retinal changes in AMD, including layer-specific thinning, microvascular rarefaction, impaired neurovascular coupling, and reactive gliosis. Such changes frequently emerge in early AMD, may precede, parallel, or exacerbate outer-retinal degeneration, and are associated with visual dysfunction not fully explained by photoreceptor loss alone. Importantly, mechanistic interactions between inner- and outer-retinal pathology support a bidirectional model of neurodegeneration, wherein region-specific vulnerability is shaped by perfusion dynamics, metabolic demands, and structural connectivity throughout the retina. Recognition of these processes expands the potential for earlier diagnosis, refined monitoring, and novel therapeutic targeting. By integrating structural, functional, and systemic insights, this review reframes AMD as a multi-layer neurovascular disease and underscores the central role of inner-retinal integrity in future AMD research and management.

Keywords:  Age-related macular degeneration; Inner-retina; Optical coherence tomography; Optical coherence tomography angiography; Retinal neurons; Retinal perfusion; Retinal remodelling

DOI:  https://doi.org/10.1016/j.preteyeres.2026.101463
Front Immunol. 2026 ;17 1759347

Spatial transcriptomic profiling identifies lacrimal-gland-epithelial cell-driven mechanisms underlying autoimmunity in Sjögren's disease.

Shivali Gupta, Athanasios Ploumakis, Nikolaos Kalavros, Sharmila Masli.

   Introduction: Sjögren's disease (SjD) is the second most prevalent rheumatic disease and is characterized by autoimmune pathology targeting the tear-producing lacrimal glands, leading to chronic ocular surface disease. Despite important advances, lacrimal gland pathology in SjD remains incompletely understood, limiting both diagnosis and treatment.
Methods: In this exploratory study, we used spatial transcriptomics to profile lacrimal glands from wild-type (C57Bl/6) mice and thrombospondin-1-deficient (TSP-1-/-) mice, a spontaneous model of SjD, to identify molecular signatures associated with the functional loss of major epithelial cell subtypes-acinar, ductal, and myoepithelial cells.
Results: Our analyses revealed gene expression patterns consistent with endoplasmic reticulum stress in acinar cells, mitochondrial dysfunction in ductal epithelial cells, secretory dysfunction in both acinar and ductal epithelial cells, and contractile impairment with profibrotic remodeling in myoepithelial cells in SjD lacrimal glands, highlighting potential early mechanisms and markers of glandular damage. Furthermore, in acinar epithelial cells, a significantly reduced expression of Pigr, which encodes the polymeric immunoglobulin receptor required for the transcytotic delivery of protective secretory IgA into tear fluid, correlated with reduced tear secretory IgA levels in SjD mice, consistent with their observed ocular surface disease.
Discussion: This finding supports the potential use of tear sIgA as a quantifiable biomarker of glandular dysfunction. By integrating spatial and cellular information, we uncovered a previously unrecognized spatial relationship between ductal epithelial cells and antigen-presenting cells in the lacrimal gland and identified a potential role for ductal epithelial cells as active drivers of inflammation by providing molecular and cellular cues that support periductal infiltrates rich in B cells and T follicular helper cells that form germinal centers and promote local autoantibody production. These findings together generate testable mechanistic hypotheses for each epithelial subtype and propose a framework for the therapeutic targeting of epithelial cells and multicellular interactions that underlie autoimmune lacrimal gland pathology in SjD.

Keywords:  Sjögren’s disease; acinar epithelial cells; antigen presenting cells; autoimmunity; duct epithelial cells; lacrimal gland; spatial transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2026.1759347