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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018658-04
Application #
8323420
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2009-09-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$367,092
Indirect Cost
$129,492
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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