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Mitochondrial Protection in Glaucomatous Optic Neuropathy

青光眼视神经病变中的线粒体保护

基本信息

批准号：
10376972
负责人：
WONKYU JU
金额：
$ 10.93万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376972
关键词：
A kinase anchoring protein Address Adenosine Triphosphate Affect Age-Years Apoptosis Apoptotic Axon Bioenergetics Blindness Calcineurin Calcium Cell Death Cell Survival Complement Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoprotection Disease Dynamin Electron Transport Complex III Functional disorder Gap Junctions Genetic Polymorphism Glaucoma Glutamates Goals Homeostasis Impairment Individual Lead Link Mediating Metabolic stress Mitochondria Modeling Nerve Degeneration Neurons Optic Nerve Outer Mitochondrial Membrane Oxidases Oxidative Phosphorylation Oxidative Stress Pathogenesis Performance Periodicity Phosphorylation Physiologic Intraocular Pressure Play Primary Open Angle Glaucoma Production Property Protein Dephosphorylation Proteins Respiration Retina Retinal Ganglion Cells Role Signal Pathway Signal Transduction Site Stress Structure Succinate dehydrogenase (ubiquinone)Superoxides Synapses Testing Therapeutic Vision Visual Pathways Visual impairment Visual system structure complex IV cytochrome c oxidase excitotoxicity improved infancy mitochondrial dysfunction neuroprotection optic nerve disorder overexpression preservation protective effect

项目摘要

Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Glaucomatous neurodegeneration is associated with impaired mitochondrial network, oxidative stress and mitochondrial dysfunction. Primary open angle glaucoma, in particular, is linked to polymorphism of mitochondrial cytochrome c oxidase (COX) subunit I of the oxidative phosphorylation (OXPHOS) complex (Cx)-IV and impaired OXPHOS Cx-I-linked respiration activity and adenosine triphosphate (ATP) synthesis. Therefore a role for compromised OXPHOS in pathogenesis of glaucoma is suggested, although the contribution of an impaired mitochondrial network to glaucoma is poorly understood. A-kinase anchoring protein 1 (AKAP1) is an outer mitochondrial membrane-targeted AKAP that regulates mitochondrial dynamics and contributes to mitochondrial network, bioenergetics and calcium homeostasis. Recently, our group has discovered that neuronal AKAP1 has potent neuroprotective properties through inhibition of mitochondrial fission dynamin-related protein 1 (Drp1), which suggests that modulation of AKAP1 could be a therapeutic approach to mitochondrial dysfunction and glaucomatous neurodegeneration. Our preliminary studies showed that 1) elevated intraocular pressure (IOP) induced loss of AKAP1, activation of calcineurin (CaN) and dephosphorylation of Drp1 at Ser637; 2) loss of AKAP1 increased CaN and total Drp1 level, and decreased Drp1 phosphorylation at Ser637 in the retina; 3) loss of AKAP1 further triggered mitochondrial fragmentation and loss, and induced mitophagosome formation in retinal ganglion cells (RGCs); 4) loss of AKAP1 deregulated OXPHOS Cxs by increasing Cx-II and decreasing Cx-III-V in the retina, leading to metabolic and oxidative stress; 5) loss of AKAP1 decreased Akt phosphorylation and activated the Bim/Bax signaling pathway in the retina; and 6) overexpression of AKAP1 led to enhanced mitochondrial activity and blocked apoptosis in RGCs, and promoted RGC survival in the setting of oxidative stress. Altogether, these findings suggest a critical role of AKAP1 in RGC protection and lead us to hypothesize that AKAP1 overexpression protects RGCs from the effects of glaucoma by promoting mitochondrial network, bioenergetics and structural integrity. We will test whether AKAP1 deficiency and its disruption of the signaling nexus impinging on mitochondria contribute to the impairment of mitochondrial bioenergetics and structure in RGCs. We will also test the protective effect of AKAP1 overexpression on mitochondrial bioenergetics and structure in glaucomatous RGCs and the therapeutic potential of AKAP1 overexpression on the central visual pathway and vision. We anticipate that these studies will enhance understanding of how AKAP1 regulates mitochondrial transport, network dynamics and bioenergetics and will support AKAP1 overexpression as a strategy to induce neuroprotection against glaucoma and optic neuropathies by improving central visual pathway functions and vision.

青光眼是全球60岁及以上人群致盲的主要原因。青光眼的