bims-mideyd 2026-10-25 papers

Adv Sci (Weinh). 2026 Oct 18. e78349

AKAP1 Protects Retinal Ganglion Cells and Preserves Vision by Improving Mitochondrial and Synaptic Health in Glaucomatous Neurodegeneration.

Tonking Bastola, Keun-Young Kim, Ziyao Shen, Guy A Perkins, Muna Poudel, Yoonjin Lim, Hyejeong Choi, Soo-Ho Choi, Mark H Ellisman, Robert N Weinreb, Won-Kyu Ju.

Glaucoma, a leading cause of irreversible blindness, is characterized by progressive loss of retinal ganglion cells (RGCs) and lacks effective neuroprotective therapies. Despite evidence implicating mitochondrial dysfunction in glaucoma, the mechanisms linking elevated intraocular pressure, synaptic dysfunction, mitochondrial failure, and RGC death remain incompletely understood. Here we identify the mitochondrial scaffold protein A-kinase anchoring protein 1 (AKAP1) as a critical regulator of RGC resilience in glaucoma. AKAP1 expression is reduced in glaucomatous retinas and correlates with disrupted mitochondrial dynamics, oxidative stress, synaptic impairment, and visual decline. AAV2-mediated restoration of AKAP1 preserves RGC survival and visual function in two independent experimental glaucoma models. These data suggest that retinal AKAP1 promotes mitochondrial fusion, cristae integrity, and bioenergetic capacity in the inner retina and in stressed cultured RGCs, and is accompanied by increased mitochondrial content in presynaptic terminals of the inner plexiform layer. Retinal AKAP1 is further associated with higher PKA abundance, normalized CaMKII and synapsin phosphorylation, preserved synaptophysin, and lower complement C1q and glial activation markers; these associations do not, by themselves, establish causality. These findings identify AKAP1 as a candidate regulator of mitochondrial and synaptic homeostasis and highlight AAV2-AKAP1 gene therapy as a promising neuroprotective strategy for vision preservation in glaucoma.

Keywords: biology; cell biology; mitochondrial biogenesis; mitochondrion; neurodegeneration; neuroprotection; neuroscience; retinal ganglion; synaptophysin

DOI: https://doi.org/10.1002/advs.78349

Extracell Vesicles Circ Nucl Acids. 2026 ;7(3): 1189-1216

Olfactory ensheathing cell-derived extracellular vesicles protect the degenerated retinal pigment epithelium by delivering phagocytosis-related proteins.

Siyu Chen, Xi Lin, Zhe Cha, Hui Gao, Jing Zhou, Shujia Huo, Cao Yang, Jiahui Kang, Lingyue Mo, Lijuan Yan, Yijian Li, Xinying Hu, Luodan A, Xiaotang Fan, Jing Xie, Haiwei Xu.

Aim: Olfactory ensheathing cells (OECs) are commonly utilized in cell-based therapies for neurodegenerative diseases and central nervous system injuries, due to their unique properties of suppressing gliosis and providing neuroprotection. Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents. This study aimed to investigate OEC-sEVs' effect on retinal degeneration. Methods: Proteomics analysis identified differentially expressed proteins between OEC-sEVs and OECs. We conducted subretinal injection of OEC-sEVs and assessed their protective mechanisms in degenerative retina. Real-time quantitative PCR and Western blot were used to detect the expression of phagocytosis-related molecules in retinal pigment epithelium (RPE) cells. Results: Proteomics analysis revealed that proteins enriched in OEC-sEVs were associated with phagocytosis. Following injection into the subretinal spaces of Royal College of Surgeons (RCS) rats, OEC-sEVs were internalized by RPE cells, leading to the transient upregulation of tyrosine-protein kinase Mer (MerTK), activation of the downstream phosphoinositide 3-kinase/Akt signaling pathway, and restoration of the phagocytic activity of RPE cells towards the photoreceptor outer segments. This delayed photoreceptor degeneration, thereby improving retinal function in RCS rats. In the ARPE-19 cell line treated with the specific MerTK inhibitor UNC2881, enhanced phagocytosis of fluorescent particles and porcine photoreceptor outer segments was observed following OEC-sEV internalization. Conclusion: OEC-sEVs were abundant in proteins associated with phagocytosis, which may partially compensate for the phagocytic deficit of the RPE cells observed in a retinitis pigmentosa rat model via the MerTK-related signaling pathway.

Keywords: MerTK; Olfactory ensheathing cells; retinal pigment epithelium; retinitis pigmentosa; small extracellular vesicles

DOI: https://doi.org/10.20517/evcna.2026.50

Cell Struct Funct. 2026 Oct 20.

Proteostasis stress alters mitochondrial levels and localization of SOD2 during cellular senescence.

Yasuhiro Takenaka, Masataka Hirasaki, Yoshihiko Kakinuma.

Proteostasis decline is a hallmark of aging and contributes to stress-induced premature senescence (SIPS) through proteotoxic stress and mitochondrial dysfunction. Although mitochondria-derived reactive oxygen species (ROS) are critically involved in SIPS, the behavior of nuclear-encoded mitochondrial antioxidant proteins under proteostasis impairment remains poorly understood. Here, we investigated the dynamics of superoxide dismutase 2 (SOD2) during SIPS induced by the proteasome inhibitor MG132 or the lysosomal inhibitor bafilomycin A1 (BAFA1) in human fibroblasts. Both MG132 and BAFA1 induced cellular senescence and caused an early reduction of SOD2 protein levels in the mitochondrial fraction without a corresponding decrease in SOD2 mRNA or total cellular SOD2 protein levels. Immunofluorescence analysis revealed that SOD2 was partially dissociated from mitochondria under these conditions, indicating impaired mitochondrial localization rather than decreased protein abundance. Quantitative colocalization analysis confirmed a significant reduction in SOD2-mitochondria overlap, which was partially restored by short-term co-treatment with antimycin A (AA), a mitochondrial electron transport chain inhibitor that attenuates excessive ROS production. Furthermore, mislocalized SOD2 was frequently associated with aggregate-like structures, and biochemical analyses demonstrated an increase in high-molecular-weight SOD2-containing complexes under proteostasis stress. These findings suggest that proteostasis disruption is associated with early changes in the intracellular distribution and aggregate-associated accumulation of SOD2, leading to a transient reduction of mitochondrial SOD2 and potentially contributing to mitochondrial oxidative imbalance and the progression of cellular senescence.Key words: cellular senescence, MnSOD, SOD2, mitochondria, oxidative stress, proteostasis, MG132, proteasome.

Keywords: MG132; MnSOD; SOD2; cellular senescence; mitochondria; oxidative stress; proteasome; proteostasis

DOI: https://doi.org/10.1247/csf.26039

iScience. 2026 Nov 20. 29(11): 117775

Dual impact of EZH1/2-targeted therapy in HTLV-1-associated inflammation: Direct and indirect mechanisms.

Yaru Zou, Koju Kamoi, Mingming Yang, Yuan Zong, Jing Zhang, Kyoko Ohno-Matsui.

Human T cell leukemia virus type 1 (HTLV-1)-associated inflammation, including uveitis, lacks effective targeted therapies. Here, we investigated whether epigenetic modulation through EZH1/2 inhibition could influence HTLV-1-related ocular inflammation using in vitro co-culture and infection models. HTLV-1 exposure increased EZH1 and EZH2 expression and the repressive histone mark H3K27me3 in retinal pigment epithelial cells. Treatment with the dual EZH1/2 inhibitor valemetostat reduced H3K27me3 levels. Valemetostat showed limited effects on cell viability and induced only modest, context-dependent apoptosis. Virological analyses showed model-dependent changes in proviral load, accompanied by reduced viral gene expression. Profiling of cytokines and chemokines revealed context-dependent modulation of inflammatory mediators. Functional assessment using p65 nuclear translocation assays indicated partial attenuation of NF-κB activation under inflammatory stimulation. Collectively, these findings suggest that EZH1/2-mediated epigenetic regulation is primarily involved in HTLV-1-related inflammatory responses, and that inhibiting EZH1/2 may be a potential approach to modulate inflammatory signaling.

Keywords: EZH1/2 inhibition; H3K27me3; HTLV-1; HTLV-1-associated uveitis; NF-κB signaling; epigenetic regulation; retinal pigment epithelial cells; valemetostat

DOI: https://doi.org/10.1016/j.isci.2026.117775

Cell Death Dis. 2026 Jul 27. pii: 900. [Epub ahead of print]17(1):

Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.

Su Jong Han, Ji Hyeon Cho, Jae Ryong Lim, Jee Hyeon Yoon, Ji Yong Park, Han Seung Chang, Su Yeol Kim, Ha Jin Kim, Seung Gyu Lee, Se Jin Mun, Jong Hwa Yun, Chang Woo Chae, Young Hyun Jung, Ho Jae Han.

Neuronal senescence, triggered by oxidative stress and inflammatory responses, is a significant risk factor for brain aging, ultimately leading to cognitive decline. Apelin-13, an exercise-induced myokine, exhibits potential neuroprotective effects by the APJ system, but its protective effects against neuronal senescence and the underlying mechanisms are unknown. This study aimed to elucidate how apelin-13 prevents D-galactose-induced neuronal senescence in SH-SY5Ys, human induced pluripotent stem cell-derived neuronal differentiated cells (iPSC-NDs), and an aging mouse model. The administration of ML233, an apelin receptor APJ agonist, attenuated brain aging and cognitive impairment in D-galactose-induced aging mice. In vitro findings showed that apelin-13 failed to scavenge the excessively generated D-galactose-induced reactive oxygen species (ROS) but prevented aging through APJ-Gαq-mediated signaling in SH-SY5Y cells. Apelin-13 activated protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) to phosphorylate AMPK, which led to the inhibition of mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 promoted the nuclear translocation of transcription factor EB (TFEB), restoring lysosomal function and autophagic flux impaired by D-galactose. Furthermore, D-galactose treatment increased the expression of GATA binding protein 4 (GATA4), a transcription factor that contributes to paracrine senescence by increasing the expression of pro-inflammatory cytokines. Neuronal autophagy restored by apelin-13 promoted GATA4 clearance, ultimately preventing pro-inflammatory cytokine-induced paracrine senescence under D-galactose conditions. Collectively, these results demonstrate that apelin-13 prevents neuronal senescence by inhibiting the mTORC1-GATA4 axis through the restoration of autophagy. Our study highlights apelin-13 as a promising therapeutic candidate for age-related cognitive decline by targeting the oxidative stress-inflammation-neuronal senescence axis through the modulation of autophagy.

DOI: https://doi.org/10.1038/s41419-026-09121-1