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 岁及以上人群失明的主要原因。青光眼神经退行性变与线粒体网络受损、氧化应激和线粒体功能障碍有关功能障碍。特别是原发性开角型青光眼与线粒体细胞色素的多态性有关氧化磷酸化 (OXPHOS) 复合物 (Cx)-IV 的 c 氧化酶 (COX) 亚基 I 和受损的 OXPHOS Cx-I 相关的呼吸活动和三磷酸腺苷 (ATP) 合成。因此，妥协的角色尽管线粒体受损也有贡献，但 OXPHOS 仍被认为是青光眼发病机制中的一个重要因素。网络对青光眼的影响知之甚少。 A-激酶锚定蛋白 1 (AKAP1) 是一种线粒体外膜靶向 AKAP 调节线粒体动力学并有助于线粒体网络，生物能量学和钙稳态。最近，我们课题组发现神经元AKAP1具有强大的功能通过抑制线粒体分裂动力相关蛋白 1 (Drp1) 发挥神经保护作用，该蛋白表明调节 AKAP1 可能是线粒体功能障碍的一种治疗方法青光眼神经变性。我们的初步研究表明1）眼压（IOP）升高诱导 AKAP1 丢失、钙调神经磷酸酶 (CaN) 激活和 Drp1 Ser637 去磷酸化； 2) 损失 AKAP1 增加 CaN 和总 Drp1 水平，并降低视网膜中 Ser637 位点的 Drp1 磷酸化； 3）损失 AKAP1 进一步触发线粒体断裂和丢失，并诱导线粒体自噬体形成视网膜神经节细胞（RGC）； 4) 通过增加 Cx-II 和减少 AKAP1 的损失来解除对 OXPHOS Cxs 的管制视网膜中的 Cx-III-V，导致代谢和氧化应激； 5) AKAP1 缺失会降低 Akt 磷酸化并激活视网膜中的 Bim/Bax 信号通路； 6) AKAP1 的过度表达导致增强线粒体活性并阻止 RGC 细胞凋亡，并在氧化环境下促进 RGC 存活压力。总而言之，这些发现表明 AKAP1 在 RGC 保护中发挥着关键作用，并促使我们做出假设 AKAP1 过度表达可通过促进线粒体网络来保护 RGC 免受青光眼的影响，生物能量学和结构完整性。我们将测试 AKAP1 缺陷是否及其对信号传导的破坏连接对线粒体的影响导致线粒体生物能和结构的损害 RGC。我们还将测试 AKAP1 过表达对线粒体生物能的保护作用和青光眼 RGC 的结构和 AKAP1 过度表达对中央视觉的治疗潜力路径和愿景。我们预计这些研究将加深对 AKAP1 如何调节的理解线粒体运输、网络动力学和生物能量学，并将支持 AKAP1 过度表达作为通过改善中枢视觉通路诱导针对青光眼和视神经病变的神经保护策略功能和愿景。