Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma

Zeng, Zhou; You, Mengling; Fan, Cong; Rong, Rong; Li, Haibo; Xia, Xiaobo

doi:10.1016/j.redox.2023.102687

Cited by 47 publications

(8 citation statements)

References 40 publications

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“…In our UPOAO model, histologic and immunohistochemical analysis demonstrates that 60 minutes of ischemia followed by 3 days or 7 days reperfusion can cause irreversible damage to the retinal structure and visual function specifically, we observed distinct alterations such as the thinning of the inner retina, substantial apoptosis of RGCs, decreased b-wave. Multiple studies on the HIOP model reported consistent results [40,44,45]. However, some typical phenotypes in HIOP model such as thinning of the outer nuclear layer and the entire neuroretina and decreased a-wave were not observed in UPOAO model.…”

Section: Discussionmentioning

confidence: 76%

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provides Insight into Pathological Processes

Wang,

Li,

Feng

et al. 2024

Preprint

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Acute retinal ischemia and ischemia-reperfusion injury are primary causes of retinal neural cell death and vision loss in retinal artery occlusion (RAO). The absence of an accurate mouse model simulating the retinal ischemic process has hampered progress in developing neuroprotective agents for RAO. A unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) mouse model was developed by employing silicone wire embolization combined with carotid artery ligation. The survival of retinal ganglion cells and visual function were evaluated to determine ischemia duration. Immunofluorescence staining, optical coherence tomography, and hematoxylin and eosin staining were utilized to assess changes in major classes of neural cells and retinal structure degeneration at two reperfusion durations. Transcriptomics was employed to investigate alterations in the pathological process of UPOAO following ischemia and reperfusion, highlighting transcriptomic differences between UPOAO and other retinal ischemia-reperfusion models. The UPOAO model successfully replicated the acute interruption of retinal blood supply seen in RAO. 60-minute ischemia was confirmed to lead the major retinal neural cells loss and visual function impairment. Notable thinning of the inner layer of the retina, especially the ganglion cell layer, was evident post-UPOAO. Temporal transcriptome analysis revealed various pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during non-reperfusion and reperfusion periods. The resident microglia within the retina and peripheral leukocytes which access to the retina were pronounced increased on reperfusion periods. Comparison of differentially expressed genes between the UPOAO and high intraocular pressure models identified specific enrichments in lipid and steroid metabolism-related genes in the UPOAO model. The UPOAO model emerges as a novel tool for the screening of pathogenic genes, promoting further therapeutic research in RAO.

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Section: Discussionmentioning

confidence: 76%

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provides Insight into Pathological Processes

Wang,

Li,

Feng

et al. 2024

Preprint

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“…Afterward, we assessed the changes of mitochondrial morphology outlined by TOMM20 antibodies according to previous studies. 45 , 48 The immunofluorescence analyses showed that, compared to the controls, the mitochondria turned out to be obviously more fragmented after LPS plus ATP stimulation, which could be mitigated by CMPK2 knockdown ( Figures S7 D and S7E). Hence, CMPK2 knockdown, followed by LPS plus ATP stimulation, could mitigate the mitochondrial fragmentation in primary mouse microglia cells.…”

Section: Resultsmentioning

confidence: 99%

Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke

Guan,

Zhu,

Song

et al. 2024

Cell Reports Medicine

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“…Previous studies have revealed that stimuli (toxic substances, ROS and aging) and inherent DNA deficiencies can impair mitochondrial structure and function, triggering the intrinsic mitochondrial pathway in glaucoma ( Fig. 3 ) ( 100 , 101 ). Meanwhile, these stimuli induce the opening of the mitochondrial permeability transition pore and hinder the mitochondrial transmembrane potential, thus accelerating the release of proapoptotic proteins, such as cytochrome c (Cytc) and apoptosis-inducing factors, such as apoptosis-inducing factor (AIF) from mitochondria into the cytoplasm ( 102 , 103 ).…”

Section: The Mechanism Of Apoptosis In Glaucomamentioning

confidence: 99%

Apoptosis in glaucoma: A new direction for the treatment of glaucoma (Review)

Xia,

Zhang

2024

Mol Med Rep

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Glaucoma is a group of progressive optic nerve disorders characterized by the loss of retinal ganglion cells, a thinner retinal nerve fibre layer and cupping of the optic disk. Apoptosis is a physiological cell death process regulated by genes and plays a crucial role in maintaining tissue homeostasis, ensuring the natural development and immune defence of organisms. Apoptosis has been associated with glaucoma and inhibiting apoptosis by activating phosphatidylinositol 3-kinase-protein kinase B or other medicines can rescue pathological changes in glaucoma. Due to the complex crosstalk of apoptosis pathways, the pathophysiological mechanism of apoptosis in glaucoma needs to be fully elucidated. The present review aimed to discuss the mechanism of cell apoptosis in glaucoma, improve the understanding of the pathophysiology of glaucoma, summarize new directions for the treatment of glaucoma and lay the foundation for new treatment strategies for glaucoma.

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Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma

Cited by 47 publications

References 40 publications

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provides Insight into Pathological Processes

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provides Insight into Pathological Processes

Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke

Apoptosis in glaucoma: A new direction for the treatment of glaucoma (Review)

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