Glaucoma is characterized by optic nerve (ON) axon loss and retinal ganglion cell (RGC) degeneration and is directly linked with elevated intraocular pressure (IOP). Although evidence of mitochondrial dysfunction was reported in patients with glaucoma, there is no direct evidence that mitochondrial dysfunction contributes to the pathogenesis of glaucoma. However, accumulation of mitochondria has been observed in the optic nerve head (ONH) of patients with glaucoma and of experimental animal models of glaucoma. We have recently identified elevated IOP-induced mitochondrial damage including alterations of mitochondrial structure and function within RGCs somas and the ONH axons in mouse models of glaucoma. The overall goal of this project is to characterize these effects and to identify new mitochondria-associated therapeutic targets that could protect against neuronal death and axon damage in glaucoma and other neurodegenerative diseases. There are three specific aims: (1) To determine whether in vitro elevated hydrostatic pressure or in vivo elevated IOP triggers breakdown of mitochondrial network, alterations of mitochondrial DNA and ultrastructural changes of cristae in RGCs somas and the ONH axons. We will examine an in vitro RGC culture system and in vivo mouse models of glaucoma to characterize the relationship of elevated IOP-induced mitochondrial changes to IOP history and mtDNA integrity and distribution. (2) To determine how in vitro elevated hydrostatic pressure or in vivo elevated IOP alters mitochondrial fusion/fission mediators that degrade mitochondrial bioenergetics and induce RGC death. These studies will extend our preliminary observation of pressure-induced alterations of OPA1 and Drp1 in RGCs in vitro and in vivo. We will correlate these OPA1 and Drp1 changes with alterations of mitochondrial fusion/fission, cellular ATP depletion, respiration deficiency, reactive oxygen species production, and apoptotic cell death in RGCs in vitro and in vivo mouse models of glaucoma. (3) To determine whether reduced Drp1 or increased OPA1 expression will block RGC loss and axon degeneration following in vitro elevated hydrostatic pressure or in vivo elevated IOP. We will transfect AAV2-OPA1 and AAV2-DrpK38A constructs into RGCs in vitro or mouse models of glaucoma in vivo and then assess RGC survival, and preservation of axons and mitochondria using imaging and molecular biological techniques as described in Aims 1 and 2. Further, we will assess RGC survival in control and OPA1 mutant mice treated with laser photocoagulation. These investigations will identify mitochondria-related new therapeutic strategies that protect RGC death and ON degeneration in glaucoma.
Evidence of mitochondrial dysfunction has been identified in a wide variety of neurodegenerative diseases including glaucoma. However, there is no evidence that mitochondrial dysfunction contributes to the pathogenesis of glaucoma. This project will address this issue and may identify new therapeutic targets that could protect against neuronal death and axon damage in glaucoma and other neurodegenerative diseases.
|Shim, Myoung Sup; Kim, Keun-Young; Noh, Mark et al. (2018) Optineurin E50K triggers BDNF deficiency-mediated mitochondrial dysfunction in retinal photoreceptor cell line. Biochem Biophys Res Commun 503:2690-2697|
|Shim, Myoung Sup; Kim, Keun-Young; Bu, Jung Hyun et al. (2018) Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes. Cell Death Dis 9:285|
|Ju, Won-Kyu; Shim, Myoung Sup; Kim, Keun-Young et al. (2018) Ubiquinol promotes retinal ganglion cell survival and blocks the apoptotic pathway in ischemic retinal degeneration. Biochem Biophys Res Commun 503:2639-2645|
|Shim, Myoung Sup; Kim, Keun-Young; Ju, Won-Kyu (2017) Role of cyclic AMP in the eye with glaucoma. BMB Rep 50:60-70|
|Shim, Myoung Sup; Takihara, Yuji; Kim, Keun-Young et al. (2016) Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration. Sci Rep 6:33830|
|Kim, K-Y; Perkins, G A; Shim, M S et al. (2015) DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma. Cell Death Dis 6:e1839|
|Ju, Won-Kyu; Kim, Keun-Young; Noh, You Hyun et al. (2015) Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes. Glia 63:736-53|
|Lee, Dongwook; Kim, Keun-Young; Shim, Myoung Sup et al. (2014) Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury. Apoptosis 19:603-14|
|Kim, S Y; Shim, M S; Kim, K-Y et al. (2014) Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis 5:e1105|
|Lee, Dongwook; Shim, Myoung Sup; Kim, Keun-Young et al. (2014) Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma. Invest Ophthalmol Vis Sci 55:993-1005|
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