Glaucoma is the leading cause of irreversible blindness and affects more than 66 million people worldwide. The observations of abnormal mitochondrial respiration and down-regulation of mitochondrial fusion-related optic atrophy 1 (OPA1) gene expression in patients with primary open angle glaucoma suggest that mitochondrial dysfunction is as an important pathophysiological mechanism, contributing to glaucoma progression. We have identified that elevated intraocular pressure (IOP) triggers excessive mitochondrial fission and cristae depletion, as well as OPA1 gene deficiency in the retina and optic nerve head (ONH) of glaucomatous DBA/2J (D2) mice. Conversely, increased OPA1 expression promotes retinal ganglion cell (RGC) survival in D2 mice. Our preliminary results indicate elevated IOP impairs mitochondrial bioenergetics by reducing cellular ATP production and by increasing reactive oxygen species generation, as well as triggers formation of S-nitrosylation of the fission-promoting protein dynamin-related protein 1 (DRP1). More importantly, inhibition of DRP1 function by overexpression of dominant-negative DRP1 K38A mutant promotes RGC survival as well as preserves mitochondrial integrity in the ONH axons of glaucomatous D2 mice. The overall goal of this competitive renewal is to further characterize the pathophysiological consequences of altered mitochondrial dynamics (fission/fusion) and to assess their significance as therapeutic targets for protecting RGCs and its axons, as well as preserving structural integrity and synapses linking RGCs and the central visual pathway, and visual function in glaucoma. There are three specific aims: 1) To characterize the pathophysiological consequences of OPA1 deficiency or S-nitrosylation of DRP1 formation in RGCs. 2) To determine the protective effect of increasing OPA1 expression or inhibiting DRP1 function to ameliorate compromised mitochondrial integrity and bioenergetics in RGCs. 3) To determine whether increasing OPA1 expression or inhibiting DRP1 function can preserve the structural integrity and synapses linking RGCs and the central visual pathway, and visual function. This proposal will enhance our understanding of the pathophysiological mechanisms of mitochondrial dysfunction in glaucomatous neurodegeneration, and offer the scientific basis for identifying and developing new therapeutic strategies that could protect not only RGCs and their axons, but also the central visual pathway against glaucomatous damage.

Public Health Relevance

Glaucoma is the leading cause of irreversible blindness and affects more than 66 million people worldwide. The overall goal of this competitive renewal is to further characterize the pathophysiological consequences of altered mitochondrial dynamics (fission/fusion) and to assess their significance as therapeutic targets for protecting retinal ganglion cells (RGCs) and its axons, as well as for preserving structural integrity and synapses linking RGCs and the central visual pathway, and for preserving visual function in glaucoma. This application will enhance our understanding of the pathophysiological mechanisms of mitochondrial dysfunction in glaucomatous neurodegeneration, and offer the scientific basis for identifying and developing new therapeutic strategies that could protect not only RGCs and their axons, but also the central visual pathway against glaucomatous damage.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY018658-05
Application #
8577596
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
2007-12-01
Project End
2018-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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; 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
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
Kushnareva, Y E; Gerencser, A A; Bossy, B et al. (2013) Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 20:353-65
Noh, Y H; Kim, K-Y; Shim, M S et al. (2013) Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell Death Dis 4:e820
Lee, Dongwook; Kim, Keun-Young; Noh, You Hyun et al. (2012) Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury. PLoS One 7:e47098
Dai, Yi; Weinreb, Robert N; Kim, Keun-Young et al. (2011) Inducible nitric oxide synthase-mediated alteration of mitochondrial OPA1 expression in ocular hypertensive rats. Invest Ophthalmol Vis Sci 52:2468-76

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