Mitochondrial Protection in Glaucomatous Optic Neuropathy

青光眼视神经病变中的线粒体保护

• 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
• 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

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.

青光眼是全世界60岁及以上人群失明的主要原因。青光眼 神经退行性变与受损的线粒体网络、氧化应激和线粒体膜电位有关。 功能障碍特别是原发性开角型青光眼，与线粒体细胞色素C的多态性有关。 氧化磷酸化（OXPHOS）复合物（Cx）-IV的c氧化酶（考克斯）亚单位I和受损的OXPHOS Cx-I连接的呼吸活性和三磷酸腺苷（ATP）合成。因此，妥协的作用 尽管线粒体受损也有贡献，但OXPHOS仍被认为是青光眼的发病机制 青光眼的发病机制尚不清楚。A激酶锚定蛋白1（AKAP 1）是一种线粒体外膜蛋白， 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，我们的研究小组发现，神经元AKAP 1具有强大的 通过抑制线粒体分裂动力蛋白相关蛋白1（Drp 1）的神经保护特性， 提示AKAP 1的调节可能是线粒体功能障碍的治疗方法， 昏迷性神经变性。我们的初步研究表明：1）眼内压（IOP）升高， 诱导AKAP 1的丢失，钙调磷酸酶（CaN）的激活和Drp 1在Ser 637的去磷酸化; 2） AKAP 1增加视网膜中CaN和总Drp 1水平，并降低Drp 1在Ser 637处的磷酸化; 3）丢失 AKAP 1的表达进一步触发线粒体断裂和丢失，并诱导线粒体吞噬体的形成。 视网膜神经节细胞（RGC）; 4）AKAP 1的丧失通过增加Cx-II和减少来解除OXPHOS Cxs的调节 视网膜中的Cx-III-V，导致代谢和氧化应激; 5）AKAP 1的缺失降低Akt磷酸化 并激活了视网膜中的Bim/Bax信号通路; 6）AKAP 1的过表达导致了视网膜中Bim/Bax信号通路的增强。 线粒体活性和阻断RGCs的凋亡，并促进RGC在氧化环境中的存活。 应力总之，这些发现表明AKAP 1在RGC保护中起关键作用，并使我们假设 AKAP 1过表达通过促进线粒体网络保护RGC免受青光眼的影响， 生物能量学和结构完整性。我们将测试AKAP 1缺陷及其对信号传导的破坏是否 碰撞线粒体的连接有助于线粒体生物能量学和结构的损伤， RGC。我们还将测试AKAP 1过表达对线粒体生物能量学的保护作用， 青光眼视网膜节细胞的结构和AKAP 1过表达对中枢视觉系统的治疗潜力 路径和愿景。我们预计这些研究将加深对AKAP 1如何调节 线粒体运输，网络动力学和生物能量学，并将支持AKAP 1过表达作为一种新的生物学机制。 改善中枢视觉通路对青光眼和视神经病变神经保护策略 功能和愿景。