Mitochondrial Protection in Glaucomatous Optic Neuropathy

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。尤其是原发性开角型青光眼与线粒体细胞色素基因多态性有关 氧化磷酸化(OXPHOS)复合体(CX)-IV的C氧化酶(COX)亚基I和受损的OXPHOS Cx-I连锁的呼吸活性和三磷酸腺苷(ATP)的合成。因此，妥协的角色 OXPHOS在青光眼的发病机制中被认为是可能的，尽管线粒体受损起到了作用 网络对青光眼的影响知之甚少。A-激酶锚定蛋白1(AKAP1)是一种外线粒体 膜靶向AKAP，调节线粒体动力学并促进线粒体网络， 生物能量学和钙稳态。最近，我们的团队发现神经元AKAP1具有强大的 通过抑制线粒体分裂动力蛋白相关蛋白1(Drp1)的神经保护作用 提示AKAP1的调节可能是治疗线粒体功能障碍和 青光眼神经变性。我们的初步研究表明：1)高眼压 诱导AKAP1的丢失，钙调神经磷酸酶(CaN)的激活和Drp1在Ser637的去磷酸化；2)丢失 AKAP1增加视网膜内CaN和总DRp1水平，降低DRp1在Ser637处的磷酸化；3)丢失 AKAP1的表达进一步引发线粒体断裂和丢失，并诱导线粒体吞噬小体形成 视网膜神经节细胞(RGC)；4)AKAP1的丢失通过增加CX-II和降低CX-II来解除对OXPHOS CXS的调控 视网膜中的CX-III-V，导致代谢和氧化应激；5)AKAP1的缺失降低了Akt的磷酸化 并激活了视网膜中的Bim/Bax信号通路；6)AKAP1的过度表达导致 氧化背景下RGC线粒体活性及抑制细胞凋亡，促进RGC存活 压力。总之，这些发现表明AKAP1在RGC保护中起着关键作用，并引导我们提出假设 AKAP1的过表达通过促进线粒体网络保护视网膜节细胞免受青光眼的影响， 生物能量学和结构完整性。我们将测试AKAP1缺陷及其对信号转导的干扰 Nexus对线粒体的冲击导致线粒体生物能和结构的损伤 RGC。我们还将测试AKAP1过表达对线粒体生物能量学和 青光眼视网膜节细胞的结构及AKAP1在中央视上过表达的治疗作用 路径和视野。我们预计这些研究将加强对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作为一种 通过改善中枢视觉通路诱导抗青光眼和视神经病变的神经保护策略 功能和愿景。

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.