bims-mideyd 2025-06-29 papers

Biomolecules. 2025 May 27. pii: 771. [Epub ahead of print]15(6):

Molecular Mechanisms of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells: Implications for Age-Related Macular Degeneration (AMD) Progression.

Na Wang, Yaqi Wang, Lei Zhang, Wenjing Yang, Songbo Fu.

Age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide, represents a complex neurodegenerative disorder whose pathogenesis remains elusive. At the core of AMD pathophysiology lies the retinal pigment epithelium (RPE), whose epithelial-mesenchymal transition (EMT) has emerged as a critical pathological mechanism driving disease progression. This transformative process, characterized by RPE cell dedifferentiation and subsequent extracellular matrix remodeling, is orchestrated through a sophisticated network of molecular interactions and cellular signaling cascades. Our review provides a comprehensive analysis of the molecular landscape underlying RPE EMT in AMD, with particular emphasis on seven interconnected pathological axes: (i) oxidative stress and mitochondrial dysfunction, (ii) hypoxia-inducible factor signaling, (iii) autophagic flux dysregulation, (iv) chronic inflammatory responses, (v) complement system overactivation, (vi) epigenetic regulation through microRNA networks, and (vii) key developmental signaling pathway reactivation. Furthermore, we evaluate emerging therapeutic strategies targeting EMT modulation, providing a comprehensive perspective on potential interventions to halt AMD progression. By integrating current mechanistic insights with therapeutic prospects, this review aims to bridge the gap between fundamental research and clinical translation in AMD management.

Keywords: TGF-β; age-related macular degeneration; autophagy; epithelial–mesenchymal transition; oxidative stress; retinal pigment epithelium

DOI: https://doi.org/10.3390/biom15060771

Cell Commun Signal. 2025 Jun 21. 23(1): 301

AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives Aβ1-40-Induced retinal pigment epithelium injury.

Xiaoxu Huang, Tongqi Li, Guanran Zhang, Jieqiong Chen, Tong Li, Shiqi Yang, Qiyu Bo, Xiaohuan Zhao, Xiaoling Wan, Xinyue Zhu, Bo Yu, Xiaodong Sun, Junran Sun.

BACKGROUND: The retinal pigment epithelium (RPE) degeneration and subsequent retinal atrophy are hallmarks of age-related macular degeneration (AMD). Amyloid-beta (Aβ), the primary component of amyloid plaques in Alzheimer's disease (AD), is also present within drusen and is considered a critical factor contributing to RPE degeneration in AMD. Recent findings indicate that Aβ-induced inflammation plays a role in RPE degeneration. The aim of this study was to explore the molecular players and the precise mechanisms involved in this process, particularly the potential role of the absent in melanoma 2 (AIM2)-like receptors (ALRs) inflammasome.
METHODS: An animal model of Aβ1-40-induced RPE injury was established. Fundus photography, electrophysiology and hematoxylin-eosin staining were used to evaluate the morphological and functional RPE damage. Transcriptome sequencing was used to detect the differentially expressed genes between Aβ1-40 group and control group. The transcriptional and protein expression levels of AIM2 pathway and RIPK family members were detected. Adeno-associated virus vector 2/2 (AAV2/2)-shAIM2 was constructed to knockdown AIM2 expression in mice RPE cells. Aβ1-40-treated ARPE-19 cells and hRPE cells were employed to analyze the regulatory effects of RIPK family on mitochondrial DNA (mtDNA) release and AIM2 pathway activation.
RESULTS: Aβ induces RPE damage through stimulation of AIM2 inflammasome and augmentation of caspase-1 and interleukin-1β (IL-1β). Knocking down AIM2 inhibits the release of inflammatory cytokines and alleviates the degeneration of the retina and RPE. Simultaneously, Aβ triggers the activation of RIPK1/RIPK3 kinases, as manifested by heightened protein expression and phosphorylation. Inhibiting RIPK1/RIPK3 phosphorylation dampens AIM2 inflammasome activity and curtails IL-1β secretion. Mechanistically, RIPK1/RIPK3 inhibition attenuates Aβ-induced Drp1(S616) hyperphosphorylation, consequently reducing mitochondrial fission and the efflux of mitochondrial DNA (mtDNA) into the cytosol. The diminished mtDNA release is responsible for attenuated AIM2 activation and subsequent inactivation of the stimulator of interferon genes (STING)/nuclear factor-kappa-B (NF-κB) signaling cascade.
CONCLUSIONS: Our study is the first to validate AIM2's contribution in Aβ-induced RPE pathology and underscore the significance of the RIPK1/RIPK3-induced mtDNA release in modulating inflammatory responses, shedding light on the underlying mechanisms and potential therapeutics of AMD.

Keywords: AIM2; Age-related macular degeneration; Amyloid β; RIPK1; RIPK3; Retinal pigment epithelial cells

DOI: https://doi.org/10.1186/s12964-025-02294-w

Nat Commun. 2025 Jun 24. 16(1): 5331

Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism.

Tae Jun Lee, Andrea Santeford, Kristen M Pitts, Carla Valenzuela Ripoll, Ryo Terao, Zhen Guo, Mualla Ozcan, Dagmar Kratky, Christina Christoffersen, Ali Javaheri, Rajendra S Apte.

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase recapitulates features of AMD. Our study defines a novel role for ApoM/S1P signaling in AMD driven by RPE lipotoxicity, mediated by cell-autonomous lysosomal lipid catabolism.

DOI: https://doi.org/10.1038/s41467-025-60830-1

Int J Mol Sci. 2025 Jun 19. pii: 5907. [Epub ahead of print]26(12):

Retinal BMI1 Expression Preserves Photoreceptors in Sodium-Iodate-Induced Oxidative Stress Models.

Zhongyang Lu, Shufeng Liu, Maria G Morales, Andy Whitlock, Ram Ramkumar, Hema L Ramkumar.

Dry age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over 50, yet no approved therapies exist for early or intermediate stages of the disease. Oxidative stress is a central driver of retinal degeneration in AMD, and sodium iodate (NaIO3)-induced injury serves as a well-characterized model of oxidative damage to the retinal pigment epithelium (RPE) and photoreceptors. BMI1, a poly-comb group protein involved in DNA repair, mitochondrial function, and cellular renewal, has emerged as a promising therapeutic target for retinal neuroprotection. We evaluated the efficacy of AAV-mediated BMI1 gene delivery in murine models using two administration routes: subretinal (SR) and suprachoroidal (SC). AAV5.BMI1 (1 × 109 vg/eye) was delivered SR in Balb/c mice and evaluated at 4 and 15 weeks post-injection. AAV8.BMI1 (5 × 109 or 1 × 1010 vg/eye) was administered SC in C57BL/6 mice and assessed at 4 weeks. Control groups received BSS or AAV8.stuffer. Following NaIO3 exposure, retinal structure and function were analyzed by optical coherence tomography (OCT), electroretinography (ERG), histology, and molecular assays. SC delivery of AAV8.BMI1 achieved the highest levels of retinal BMI1 expression with no evidence of local or systemic toxicity. Treated eyes showed dose-dependent preservation of outer nuclear layer (ONL) thickness and significantly improved ERG responses indicating structural and functional protection. These findings support SC AAV.BMI1 gene therapy as a promising, minimally invasive, and translatable approach for early intervention in intermediate AMD.

Keywords: AAV gene therapy; BMI1; age-related macular degeneration; retina; retinal pigment epithelium; sodium iodate

DOI: https://doi.org/10.3390/ijms26125907