Mitochondrial Dysfunction in Glaucomatous Optic Neuropathy

摘要 青光眼是导致不可逆转失明的主要原因，全世界有6600万人患有青光眼。 线粒体呼吸异常及线粒体融合相关基因下调的观察 视神经萎缩1(OPA1)基因在开角型青光眼患者中的表达 线粒体功能障碍是青光眼发病的重要病理生理机制。 进步。我们已经发现，眼压升高会触发线粒体过多 视网膜和视神经头(ONH)的分裂和脊耗竭以及OPA1基因缺陷 青光眼DBA/2J(D2)小鼠。相反，OPA1表达增加促进视网膜神经节细胞 (RGC)D2小鼠存活。我们的初步结果表明，高眼压损害了线粒体的生物能量学 通过减少细胞ATP的产生和增加活性氧物种的产生以及触发 裂变促进蛋白动力蛋白相关蛋白1的S亚硝化形成。更多 重要的是，显性阴性的Drp1 K38A突变体过表达对Drp1功能的抑制促进了 在青光眼D2小鼠的ONH轴突中，RGC存活并保持线粒体完整性。这个 这一竞争性更新的总体目标是进一步表征肺炎的病理生理后果 改变线粒体动力学(分裂/融合)并评估其作为治疗靶点的意义 保护视网膜节细胞及其轴突，以及保持结构完整性和连接视网膜节细胞和 中枢视觉通路与青光眼视功能的关系。有三个具体目标：1)描述 视网膜节细胞中OPA1缺乏或DRP1形成的S亚硝化的病理生理后果。2)至 确定上调OPA1表达或抑制DRp1功能改善的保护作用 视网膜节细胞线粒体完整性和生物能量学受损。3)确定增加OPA1是否 表达或抑制Drp1功能可以保护RGC和RGC之间的结构完整性和突触 中枢视觉通路和视觉功能。这项建议将加深我们对 青光眼神经变性中线粒体功能障碍的病理生理机制 确定和开发新的治疗策略的科学基础不仅可以保护RGC 以及它们的轴突，也是对抗青光眼损害的中央视觉通路。

ABSTRACT Glaucoma is the leading cause of irreversible blindness and affects more than 66 million people worldwide. The observations of abnormal mitochondrial respiration and down-regulation of mitochondrial fusion-related optic atrophy 1 (OPA1) gene expression in patients with primary open angle glaucoma suggest that mitochondrial dysfunction is as an important pathophysiological mechanism, contributing to glaucoma progression. We have identified that elevated intraocular pressure (IOP) triggers excessive mitochondrial fission and cristae depletion, as well as OPA1 gene deficiency in the retina and optic nerve head (ONH) of glaucomatous DBA/2J (D2) mice. Conversely, increased OPA1 expression promotes retinal ganglion cell (RGC) survival in D2 mice. Our preliminary results indicate elevated IOP impairs mitochondrial bioenergetics by reducing cellular ATP production and by increasing reactive oxygen species generation, as well as triggers formation of S-nitrosylation of the fission-promoting protein dynamin-related protein 1 (DRP1). More importantly, inhibition of DRP1 function by overexpression of dominant-negative DRP1 K38A mutant promotes RGC survival as well as preserves mitochondrial integrity in the ONH axons of glaucomatous D2 mice. The overall goal of this competitive renewal is to further characterize the pathophysiological consequences of altered mitochondrial dynamics (fission/fusion) and to assess their significance as therapeutic targets for protecting RGCs and its axons, as well as preserving structural integrity and synapses linking RGCs and the central visual pathway, and visual function in glaucoma. There are three specific aims: 1) To characterize the pathophysiological consequences of OPA1 deficiency or S-nitrosylation of DRP1 formation in RGCs. 2) To determine the protective effect of increasing OPA1 expression or inhibiting DRP1 function to ameliorate compromised mitochondrial integrity and bioenergetics in RGCs. 3) To determine whether increasing OPA1 expression or inhibiting DRP1 function can preserve the structural integrity and synapses linking RGCs and the central visual pathway, and visual function. This proposal will enhance our understanding of the pathophysiological mechanisms of mitochondrial dysfunction in glaucomatous neurodegeneration, and offer the scientific basis for identifying and developing new therapeutic strategies that could protect not only RGCs and their axons, but also the central visual pathway against glaucomatous damage.