bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2026–04–05
eight papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa
  1. Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation.
  2. Maresin 1 activates autophagy through SIRT1/PPAR-γ signaling to mitigate high glucose-induced pyroptosis in human retinal pigment epithelial cells.
  3. Cell-Type-Dependent Metabolic Compensation Preserves Photoreceptor Survival Through Pyruvate Kinase Isoform Balance.
  4. Curcumin protects retinal photoreceptors in Glaucoma by activating prostaglandin D2 synthase-dependent NRF2 signaling.
  5. MiR-335-5p as a potential biomarker of wet age-related macular degeneration.
  6. REP-1 deficiency induces aberrant mitochondrial metabolic rewiring from glycolysis to lipid oxidation in CHM disease.
  7. Retinal pigment epithelium pseudopods reach across the divide to maintain photoreceptor performance and save vision.
  8. Quantitative fundus autofluorescence in age-related macular degeneration.
  1. bioRxiv. 2026 Mar 23. pii: 2026.03.19.712761. [Epub ahead of print]
    Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation.
    Hilal Ahmad Mir, Gaddam Mahesh, Arunan Palanimuthu, Christopher L Cioffi, Konstantin Petrukhin.
      Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly individuals for which no effective treatments are currently available. The photoreceptor loss in dry AMD is secondary to the demise of the retinal pigment epithelium (RPE) cells. The accumulation of extracellular deposits, known as drusen, resulting in part from deficient lysosomal and autophagosomal degradation, is a key feature of dry AMD pathogenesis. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains proteostasis by targeting specific cytosolic proteins for lysosomal translocation and degradation. LAMP2A (lysosome-associated membrane protein 2A) functions as the key lysosomal receptor required for CMA. Using Lamp2a knockout mouse, we show that selective CMA dysfunction recapitulates AMD-like pathologies, including sub-RPE lipid and protein deposits, RPE atrophy, Bruch's membrane thickening, and impaired autophagic activity. Furthermore, we identify large-conductance Ca²⁺-activated K⁺ (BK) channels as a therapeutic target for restoring autophagic activity. Mechanistically, pharmacological activation of BK channels with the small-molecule agonist GLA-1-1 enhances macroautophagy and stimulates autophagic flux by promoting autophagosome-lysosome fusion. Importantly, oral administration of GLA-1-1 in markedly attenuates structural, functional, and molecular retinal abnormalities in Lamp2a -deficient mice, suggesting that pharmacological activation of macroautophagy through facilitating autophagosome-lysosome fusion can partially compensate for CMA deficiency. Together, these findings demonstrate that pharmacological activation of macroautophagy can ameliorate the retinal phenotype resulting from CMA dysfunction and support BK channel activation by GLA-1-1 as a promising therapeutic strategy for dry AMD.
    DOI:  https://doi.org/10.64898/2026.03.19.712761
  2. Exp Ther Med. 2026 May;31(5): 141
    Maresin 1 activates autophagy through SIRT1/PPAR-γ signaling to mitigate high glucose-induced pyroptosis in human retinal pigment epithelial cells.
    Jun Zhang, Ding Zhao, Yuanqing Zhang, Haoxiang Sun, Zhipeng Yan, Haiyan Sun.
      Accumulating evidence suggests that maresin 1 (MaR1), a docosahexaenoic acid-derived specialized pro-resolving lipid mediator, safeguards ARPE-19 cells against high glucose (HG)-induced ferroptosis, with potential relevance in preventing the onset and progression of diabetic retinopathy (DR). Building upon this observation, the present study aimed to elaborate on the functional role of MaR1 in DR and explore the underlying mechanisms mediating its protective effects. ARPE-19 cells were exposed to HG to mimic DR in vitro and treated with varying doses of MaR1. An MTT assay was conducted to assess cell viability, while ELISA was used to measure the levels of inflammatory factors in the cells. Monodansylcadaverine staining was used to evaluate autophagic flux. Additionally, immunofluorescence and western blot assays were used to detect the expression of proteins associated with pyroptosis, autophagy and the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway. To further investigate the mechanism underlying the actions of MaR1, ARPE-19 cells were pretreated with a SIRT1 inhibitor (EX-527) or an autophagy inhibitor (3-MA) before the aforementioned treatments were administered. The findings revealed that MaR1 rescued cell viability and attenuated the expression and secretion of pro-inflammatory cytokine levels (specifically IL-1β and IL-18) in HG-challenged ARPE-19 cells in a dose-dependent manner, while also alleviating the HG-induced reduction in autophagic flux. Pretreatment with MaR1 further reversed the HG-mediated downregulation of beclin 1, LC3-II/I, SIRT1 and PPAR-γ, alongside the HG-triggered upregulation of p62, gasdermin D N-terminal, cleaved caspase-1, NLR family pyrin domain containing 3, apoptosis-associated speck-like protein containing a CARD and IL-18, as demonstrated through immunofluorescence and western blot analyses. Notably, an autophagy inhibitor blunted the regulatory effects of MaR1 on pyroptosis, whereas a SIRT1 inhibitor abrogated the protective actions of MaR1 against inflammation and pyroptosis, as well as its modulation of autophagy, as demonstrated by measuring key molecular markers of pyroptosis, inflammation and autophagy in treated ARPE-19 cells. Overall, the results indicated that MaR1 mitigated HG-induced pyroptosis in human retinal pigment epithelial cells, potentially by upregulating the SIRT1/PPAR-γ signaling pathway to reinstate autophagy, thus ameliorating DR-associated damage.
    Keywords:  ARPE-19 cells; autophagy; high glucose; maresin 1; pyroptosis; sirtuin 1/peroxisome proliferator-activated receptor-γsignaling
    DOI:  https://doi.org/10.3892/etm.2026.13134
  3. FASEB J. 2026 Apr 15. 40(7): e71730
    Cell-Type-Dependent Metabolic Compensation Preserves Photoreceptor Survival Through Pyruvate Kinase Isoform Balance.
    Ammaji Rajala, Larissa J Trevino, Tyler M Black, Raju V S Rajala.
      Photoreceptors depend on aerobic glycolysis to meet the high biosynthetic demand required for continuous outer segment renewal. Disruption of this metabolic program is increasingly recognized as a contributor to retinal degeneration; however, the coordinated roles of key glycolytic enzymes across retinal cell types remain incompletely understood. Pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) are central regulators of aerobic glycolysis; however, the mechanisms by which their interplay supports retinal homeostasis remain unclear. Here, we investigated the effects of selectively deleting LDHA alone or in combination with PKM2 in retinal neurons. Rod-specific deletion of LDHA, as well as combined deletion of LDHA and PKM2 in rods, led to progressive photoreceptor degeneration, accompanied by structural disorganization and functional impairment. Loss of LDHA reduced PKM2 expression and induced compensatory upregulation of PKM1; however, PKM1 levels did not reach those of PKM2, correlating with increased susceptibility to degeneration. In contrast, deletion of both LDHA and PKM2 throughout the retina led to robust PKM1 induction to levels comparable to those of PKM2 and was associated with preservation of retinal structure and function. Translating ribosome affinity purification demonstrated that LDHA, LDHB, PKM1, and PKM2 are expressed across multiple retinal cell types, and metabolic analyses revealed that non-rod neurons contribute substantially to retinal lactate production. We propose a PKM isoform balance threshold model in which retinal outcome depends on the level of PKM1 compensation following PKM2 loss. When PKM1 reaches levels comparable to PKM2, retinal structure and function are preserved; insufficient compensation results in degeneration. These findings highlight cell-type-dependent metabolic compensation and pyruvate kinase isoform balance as key determinants of retinal integrity and photoreceptor survival.
    Keywords:  LDHA; PKM1; PKM2; neurodegeneration; photoreceptors; retinal metabolism
    DOI:  https://doi.org/10.1096/fj.202505064R
  4. Cell Signal. 2026 Mar 31. pii: S0898-6568(26)00168-3. [Epub ahead of print] 112516
    Curcumin protects retinal photoreceptors in Glaucoma by activating prostaglandin D2 synthase-dependent NRF2 signaling.
    Ying Wang, Yu Ma, Shuo Zhang, Lili Nie.
      Glaucoma, a leading cause of irreversible blindness, involves oxidative stress-mediated damage to retinal photoreceptors. This study elucidates the molecular mechanism by which curcumin, a natural compound, protects retinal cells in glaucoma. Molecular docking and biochemical assays revealed that curcumin binds prostaglandin D2 synthase (PTGDS) with high affinity, leading to marked upregulation of PTGDS expression. In vitro experiments using H2O2-treated 661 W retinal cells showed that PTGDS overexpression suppressed reactive oxygen species (ROS) accumulation, inflammation, and apoptosis while enhancing proliferation. Transcriptomic profiling showed that PTGDS knockdown disrupted nuclear factor erythroid 2-related factor 2 (NRF2) signaling and downregulated key antioxidant genes. Mechanistically, curcumin-induced PTGDS expression activated NRF2, increased phosphorylation of AMP-activated protein kinase (AMPK) and ERK, upregulated Bcl-2, and inhibited Bax and caspase-3 cleavage. These effects were abolished by PTGDS knockdown. In vivo validation using a paraquat-induced glaucoma mouse model confirmed that curcumin improved visual function (via pattern electroretinography, optokinetic response, and visual evoked potentials), reduced retinal oxidative stress markers (malondialdehyde, superoxide dismutase, glutathione), and attenuated inflammatory cytokines (Interleukin [IL]-1β, Tumor Necrosis Factor Alpha [TNF-α]). PTGDS knockdown negated these therapeutic benefits. Together, these findings establish PTGDS as a critical mediator of curcumin-induced NRF2 activation, highlighting a novel cross-species neuroprotective pathway and a promising therapeutic target for glaucoma.
    Keywords:  Curcumin; Glaucoma; Neuroprotection; Nuclear factor erythroid 2-related factor 2 signaling pathway; Oxidative stress; Prostaglandin D2 synthase
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112516
  5. Clin Exp Optom. 2026 Mar 31. 1-11
    MiR-335-5p as a potential biomarker of wet age-related macular degeneration.
    Yanrong Chen, Zhaode Zhang, Jingjing Wu, Yuqing Wang, Shuhua Lin.
       CLINICAL RELEVANCE: Early diagnosis and intervention are of vital importance in delaying the irreversible vision loss caused by wet age-related macular degeneration (wAMD).
    BACKGROUND: wAMD can lead to blindness in severe cases. At present, the pathogenesis of wAMD is still unclear, so a new biomarker is needed to study wAMD.
    METHODS: A total of 190 subjects were included in this study, including the control group (n = 90) and the wAMD group (n = 100). The expression of miR-335-5p and the diagnostic value of miR-335-5p in wAMD were analysed. ARPE-19 cells treated with 300 µM t-BHP for 24 h or 600 µM H2O2 for 24 h were selected as oxidative damage models. MiR-335-5p mimic and miR-335-5p inhibitor were transfected into oxidative damage models to up-regulate and down-regulate miR-335-5p, and then proliferation and apoptosis were measured. Targetscan was used to forecast the target of miR-335-5p and gain VEGFA, which was confirmed by the dual-luciferase reporter system. MiR-335-5p and VEGFA were overexpressed in oxidative damage models to detect the role of both in wAMD.
    RESULTS: MiR-335-5p was reduced and may have high diagnostic value in wAMD. MiR-335-5p was a risk factor for wAMD. In the oxidative damage models, overexpressed miR-335-5p increased the cell viability and decreased the apoptosis, while the inhibition of miR-335-5p was reversed. VEGFA was the target of miR-335-5p and was negatively regulated by miR-335-5p in the oxidative damage models. VEGFA and miR-335-5p were negatively correlated in wAMD.
    CONCLUSION: MiR-335-5p may have a high diagnostic value in wAMD, suggesting that miR-335-5p might be a biomarker of wAMD. VEGFA was the target of miR-335-5p, and the two were negative correlation in wAMD. MiR-335-5p regulates VEGFA secretion in RPE cells, thereby indirectly participating in the core pathological process of wAMD.
    Keywords:  Biomarker; VEGFA; diagnosis; miR-335-5p; wet age-related macular degeneration
    DOI:  https://doi.org/10.1080/08164622.2026.2639834
  6. Cell Death Dis. 2026 Mar 30.
    REP-1 deficiency induces aberrant mitochondrial metabolic rewiring from glycolysis to lipid oxidation in CHM disease.
    Sara Buonocore, Giuliana Giamundo, Chiara Barone, Iolanda Carratù, Giovanna Trinchese, Giovanni Andrea Vitale, Gianluca Fasciolo, Marcello Ziaco, Paola Venditti, Angelo Fontana, Maria Pina Mollica, Dario Antonini, Ivan Conte.
      Choroideremia (CHM) is a hereditary retinal degenerative disorder characterized by progressive dysfunction of the retinal pigment epithelium (RPE) and photoreceptors with no available therapy. Despite the recognized genetic basis of CHM, the metabolic pathways driving disease progression remain poorly defined. By investigating REP-1 deficiency in CHM disease, our study reveals a previously unrecognized role for REP-1 in regulating GLUT-1 and GLUT-4 membrane trafficking, controlling glucose uptake, and reprograming mitochondrial metabolism toward lipid oxidation. This chronic metabolic shift results in reduced glycolytic flux, elevated oxidative stress, and compromised ATP production, culminating in a progressive retinal dystrophy. Notably, pharmacological restoration of GLUT trafficking via leptin administration re-established glucose uptake and mitochondrial function, rescuing cellular energetics both in vitro and in vivo. These findings establish REP-1 as a key regulator of retinal metabolic homeostasis and suggest that targeting glucose-lipid metabolic rewiring may represent a novel therapeutic strategy for CHM and related retinal dystrophies.
    DOI:  https://doi.org/10.1038/s41419-026-08592-6
  7. J Clin Invest. 2026 Apr 01. pii: e205127. [Epub ahead of print]136(7):
    Retinal pigment epithelium pseudopods reach across the divide to maintain photoreceptor performance and save vision.
    Akrit Sodhi.
      
    DOI:  https://doi.org/10.1172/JCI205127
  8. Surv Ophthalmol. 2026 Mar 31. pii: S0039-6257(26)00051-2. [Epub ahead of print]
    Quantitative fundus autofluorescence in age-related macular degeneration.
    Leon von der Emde, Gregor S Reiter, Merten Mallwitz, Anna Sophia Jauch, Katharina Wall, Frank G Holz, Andreas Pollreisz, Thomas Ach.
      Fundus autofluorescence captures the fluorescence of the retina, specifically the retinal pigment epithelium (RPE). Within the RPE, fluorophores, including lipofuscin, melanolipofuscin, and melanosomes, fluoresce when excited by light of varying wavelengths. Quantitative fundus autofluorescence (QAF), which has been implemented using blue excitation light, enables mapping and quantifying lipofuscin and melanolipofuscin fluorescence. This is achieved by using a reference bar to standardize measurements. The technical functionality of QAF relies on repeatability and high image quality. Multicenter studies, however, indicate variability. Age-related lens opacities also affect QAF, necessitating individualized correction formulas for accuracy. Accordingly, this review focuses on the development and application of QAF, addressing technical considerations and its relevance to structural and cellular changes in age-related macular degeneration (AMD), and highlighting how QAF can provide clinically meaningful information for AMD diagnosis and therapy monitoring. In AMD, numerous independent studies have found reduced autofluorescence at the posterior pole and as AMD progresses autofluorescence further decreases. Typical AMD lesions, such as subretinal drusenoid deposits, have been associated with significant QAF reduction. On a cellular level, granule aggregation and degranulation are identified as histological correlates. Subcellularly, technologies like serial block-face scanning electron and structured illumination microscopy have revealed a reduced lipofuscin volumetric density and RPE dysmorphia associated with AMD's reduced autofluorescence. New software tools enhance QAF's potential for detailed lesion analysis. Future advancements in QAF include integrating new excitation wavelengths and combining quantified emission spectra and fluorescence lifetimes to improve early detection of AMD-related changes. Despite challenges, QAF continues to evolve, promising better insights into retinal health and disease.
    Keywords:  AMD; fundus autofluorescence; geographic atrophy; quantitative autofluorescence; retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.survophthal.2026.03.018
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