Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes

Ju, Won‐Kyu; Kim, Keun Young; Noh, You Hyun; Hoshijima, Masahiko; Lukas, Thomas J.; Ellisman, Mark H.; Weinreb, Robert N.; Perkins, Guy

doi:10.1002/glia.22781

Cited by 60 publications

(58 citation statements)

References 78 publications

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“…Only recently has a specific role for astrocytes in this process received any attention. Astrocytes in the ONH have been implicated in elevated intraocular pressure and ganglion cell death in glaucoma (Cooper et al, 2015; Dai et al, 2012; Ju et al, 2015). Although the implications are not clear, here we show that there are similar structural changes in ONH astrocytes in response to retinal detachment.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte structural reactivity and plasticity in models of retinal detachment

Luna

Keeley

Reese

et al. 2016

Experimental Eye Research

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Although retinal neurodegenerative conditions such as age-related macular degeneration, glaucoma, diabetic retinopathy, retinitis pigmentosa, and retinal detachment have different etiologies and pathological characteristics, they also have many responses in common at the cellular level, including neural and glial remodeling. Structural changes in Müller cells, the large radial glia of the retina in retinal disease and injury have been well described, that of the retinal astrocytes remains less so. Using modern imaging technology to describe the structural remodeling of retinal astrocytes after retinal detachment is the focus of this paper. We present both a review of critical literature as well as novel work focusing on the responses of astrocytes following rhegmatogenous and serous retinal detachment. The mouse presents a convenient model system in which to study astrocyte reactivity since the Müller cell response is muted in comparison to other species thereby allowing better visualization of the astrocytes. We also show data from rat, cat, squirrel, and human retina demonstrating similarities and differences across species. Our data from immunolabeling and dye-filling experiments demonstrate previously undescribed morphological characteristics of normal astrocytes and changes induced by detachment. Astrocytes not only upregulate GFAP, but structurally remodel, becoming increasingly irregular in appearance, and often penetrating deep into neural retina. Understanding these responses, their consequences, and what drives them may prove to be an important component in improving visual outcome in a variety of therapeutic situations. Our data further supports the concept that astrocytes are important players in the retina’s overall response to injury and disease.

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Section: Discussionmentioning

confidence: 99%

Astrocyte structural reactivity and plasticity in models of retinal detachment

Luna

Keeley

Reese

et al. 2016

Experimental Eye Research

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“…Evidence from our group and others indicates that compromised mitochondrial dynamics, metabolic stress and mitochondrial dysfunction by glaucomatous insults such as elevated intraocular pressure (IOP) and oxidative stress are critical to RGC loss in experimental glaucoma [8][9][10][11][12][13][14][15][16][17][18][19] . Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying the impairment of mitochondrial structure and function in glaucoma are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Edwards

Perkins

Kim

et al. 2019

Preprint

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AbstractImpairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases of CaN and total Drp1 level, as well as a decrease of Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

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“…The mechanisms involved in RGC death in glaucoma are complicated. The elevated intraocular pressure (IOP) is considered to be the major risk factor (Osborne, 2008; Ju et al, 2015; Yang et al, 2016), and lowering the IOP is thus far the only relatively effective treatment clinically (Chen et al, 2013; Itakura et al, 2015). However, lowering the IOP is not sufficient to prevent or delay progressive vision loss, and the molecular mechanisms underlying accelerated RGC loss, even when the raised IOP is lowered to a normal level for many years, remain poorly understood (Gupta and Yücel, 2007; Osborne, 2010).…”

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confidence: 99%

“…The neuroprotective effects against elevated pressure exerted by lithium chloride and iNOS were involved in regulating the mitochondrial dynamic proteins DRP1 and OPA1, respectively (Dai et al, 2011). Recently, Ju et al (2015) found that increasing mitochondrial fission, volume density and length protected astrocytes in glaucomatous neurodegeneration. Moreover, many studies have indicated that mitochondrial abnormalities occur in primary open-angle glaucoma patients, including increasing mitochondrial DNA (mtDNA) pathogenic mutations and content as well as decreasing mitochondrial respiratory activity (Abu-Amero et al, 2011; Nucci et al, 2013; Sundaresan et al, 2015).…”

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confidence: 99%

High Pressure-Induced mtDNA Alterations in Retinal Ganglion Cells and Subsequent Apoptosis

Zhang

Gao

Sun

et al. 2016

Front. Cell. Neurosci.

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Purpose: Our previous study indicated that mitochondrial DNA (mtDNA) damage and mutations are crucial to the progressive loss of retinal ganglion cells (RGCs) in a glaucomatous rat model. In this study, we examined whether high pressure could directly cause mtDNA alterations and whether the latter could lead to mitochondrial dysfunction and RGC death.Methods: Primary cultured rat RGCs were exposed to 30 mm Hg of hydrostatic pressure (HP) for 12, 24, 48, 72, 96 and 120 h. mtDNA alterations and mtDNA repair/replication enzymes OGG1, MYH and polymerase gamma (POLG) expressions were also analyzed. The RGCs were then infected with a lentiviral small hairpin RNA (shRNA) expression vector targeting POLG (POLG-shRNA), and mtDNA alterations as well as mitochondrial function, including complex I/III activities and ATP production were subsequently studied at appropriate times. Finally, RGC apoptosis and the mitochondrial-apoptosis pathway-related protein cleaved caspase-3 were detected using a Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and western blotting, respectively.Results: mtDNA damage was observed as early as 48 h after the exposure of RGCs to HP. At 120 h after HP, mtDNA damage and mutations significantly increased, reaching >40% and 4.8 ± 0.3-fold, respectively, compared with the control values. Twelve hours after HP, the expressions of OGG1, MYH and POLG mRNA in the RGCs were obviously increased 5.02 ± 0.6-fold (p < 0.01), 4.3 ± 0.2-fold (p < 0.05), and 0.8 ± 0.09-fold (p < 0.05). Western blot analysis showed that the protein levels of the three enzymes decreased at 72 and 120 h after HP (p < 0.05). After interference with POLG-shRNA, the mtDNA damage and mutations were significantly increased (p < 0.01), while complex I/III activities gradually decreased (p < 0.05). Corresponding decreases in membrane potential and ATP production appeared at 5 and 6 days after POLG-shRNA transfection respectively (p < 0.05). Increases in the apoptosis of RGCs and cleaved caspase-3 protein expression were observed after mtDNA damage and mutations.Conclusions: High pressures could directly cause mtDNA alterations, leading to mitochondrial dysfunction and RGC death.

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Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes

Cited by 60 publications

References 78 publications

Astrocyte structural reactivity and plasticity in models of retinal detachment

Astrocyte structural reactivity and plasticity in models of retinal detachment

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

High Pressure-Induced mtDNA Alterations in Retinal Ganglion Cells and Subsequent Apoptosis

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