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：
10441589
负责人：
WONKYU JU
金额：
$ 48.5万
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/10441589
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 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60岁及以上的个人在全球失明的主要原因。青光眼神经变性与线粒体网络受损，氧化应激和线粒体有关功能障碍。尤其是主要的开角青光眼与线粒体细胞色素的多态性有关 C氧化磷酸化（OXPHOS）复合物（CX）-IV和OXPHOS受损的C氧化酶（COX）亚基I CX-I连接的呼吸活性和三磷酸腺苷（ATP）合成。因此，妥协的角色尽管线粒体受损的贡献对青光眼的网络知之甚少。 A-激酶锚定蛋白1（AKAP1）是外部线粒体对膜靶向的AKAP调节线粒体动力学并有助于线粒体网络，生物能学和钙稳态。最近，我们的小组发现神经元AKAP1具有有效通过抑制线粒体裂变动力蛋白相关蛋白1（DRP1），神经保护特性，该特性表明AKAP1的调节可能是线粒体功能障碍的治疗方法青光眼神经变性。我们的初步研究表明，1）眼内压（IOP）升高在Ser637处诱导的AKAP1丢失，钙调神经酶（CAN）的激活（CAN）和DRP1的去磷酸化； 2）损失 AKAP1增加了罐头和总DRP1水平，并在视网膜中Ser637时DRP1磷酸化降低； 3）损失 AKAP1进一步触发了线粒体的碎片和损失，并诱导了线粒体形成视网膜神经节细胞（RGC）； 4）通过增加CX-II并减少AKAP1失控的OXPHOS CXS 视网膜中的CX-III-V，导致代谢和氧化应激； 5）AKAP1的损失降低了AKT磷酸化并激活视网膜中的BIM/BAX信号通路； 6）AKAP1的过表达导致增强线粒体活性并阻断RGC中的凋亡，并在氧化的情况下促进RGC存活率压力。总之，这些发现表明AKAP1在RGC保护中起着至关重要的作用，并导致我们假设 AKAP1过表达通过促进线粒体网络保护RGC免受青光眼的影响，生物能学和结构完整性。我们将测试AKAP1缺陷及其信号的破坏是否构成线粒体的联系有助于线粒体生物能和结构的损害 RGCS。我们还将测试AKAP1过表达对线粒体生物能和的保护作用青光眼RGC中的结构和AKAP1过表达在中央视觉上的治疗潜力途径和视力。我们预计这些研究将增强对AKAP1如何调节的理解线粒体传输，网络动力学和生物能学，并将支持AKAP1过表达通过改善中央视觉途径来诱导针对青光眼和视觉神经病的神经保护作用的策略功能和视野。