Roles of Mitochondrial Fusion in Optic Neuropathy

描述（由申请人提供）：线粒体结构的调节对多种细胞活动至关重要，包括ATP合成、代谢、离子稳态、细胞命运决定、凋亡和衰老。线粒体在发育过程中获得特殊的形状，并在不同的生理条件下戏剧性地重组其结构。越来越多的证据表明，线粒体融合在线粒体结构的建立、维持和重塑中起着重要作用。线粒体结构异常与常染色体显性视萎缩和青光眼这两种主要致盲原因有关。常染色体显性视神经萎缩是由Opa1基因突变引起的，该基因编码线粒体融合所需的动力蛋白相关GTPase。此外，Opa1的多态性通常与正常张力性青光眼和高张力性青光眼有关。这些神经退行性疾病的特点是视网膜神经节细胞的逐渐丧失。然而，目前尚不清楚Opa1的缺陷是如何导致神经节细胞变性的。我们的长期目标是了解Opa1的功能障碍是如何导致神经节细胞退化的。为了实现这一目标，我们使用Cre-loxP系统生成了视网膜特异性小鼠的Opa1基因敲除。在本研究中，我们将利用该动物模型研究Opa1在视网膜中的生理作用，并确定常染色体显性视萎缩和青光眼的发病机制。我们的初步研究表明，视网膜特异性缺失的Opa1在神经节细胞中产生缺陷，与视神经病变的临床特征相似。在Aim 1中，我们将分析视网膜特异性敲除Opa1的视网膜发育和形态发生。这种遗传分析将揭示在这些过程中失去Opa1的后果。在Aim 2中，我们将研究Opa1在视网膜线粒体结构和功能中的作用。对Opa1基因敲除小鼠的细胞生物学分析将确定视网膜神经变性的细胞机制。我们的研究结果将为视神经病变的发病机制提供新的见解，并可能帮助我们开发基于线粒体的治疗方法。

DESCRIPTION (provided by applicant): Regulation of mitochondrial structure is essential for a variety of cellular activities including ATP synthesis, metabolism, ion homeostasis, cell fate determination, apoptosis, and aging. Mitochondria acquire specialized shapes during development and dramatically reorganize their structures in response to different physiological conditions. An increasing number of evidence demonstrates that mitochondrial fusion plays important roles in establishing, maintaining and remodeling mitochondrial structure. Abnormalities of mitochondrial structure are associated with the two major causes of blindness, autosomal dominant optic atrophy and glaucoma. Autosomal dominant optic atrophy results from mutations of the Opa1 gene, which encodes a dynamin-related GTPase required for mitochondrial fusion. Also polymorphisms of Opa1 are often associated with normal tension glaucoma and high tension glaucoma. These neurodegenerative diseases are characterized by progressive loss of retinal ganglion cells. However, it is largely unknown how defects in Opa1 cause degeneration of ganglion cells. Our long term goal is to understand how Opa1's dysfunction leads to degeneration of ganglion cells. Toward this goal, we have generated retina-specific mouse knockouts for Opa1 using the Cre-loxP system. In this proposed research, we will use this animal model to study physiological roles of Opa1 in the retina, and determine the pathogenesis of autosomal dominant optic atrophy and glaucoma. Our initial investigation demonstrated that retina-specific deletion of Opa1 produces defects in ganglion cells similar to clinical characteristics of the optic neuropathies. In Aim 1, we will analyze retinal development and morphogenesis in retina-specific knockout of Opa1. This genetic analysis will reveal the consequence of loss of Opa1 in these processes. In Aim 2, we will examine roles of Opa1 in mitochondrial structure and function in retinas. This cell biological analysis of Opa1 knockout mice will determine cellular mechanisms underlining neurodegeneration in retinas. The outcomes of our research will provide novel insights into the pathogenesis of the optic neuropathies and may help us to develop mitochondria-based therapy for them. PUBLIC HEALTH RELEVANCE: Autosomal dominant optic atrophy and glaucoma are associated with mutations of the Opa1 gene, which encodes a mitochondrial protein required for mitochondrial fusion. We study the pathogenesis of these two major optic neuropathies. Our long term goal is to understand how mitochondrial fusion controls mitochondrial structure and function and how defects in mitochondrial fusion cause the eye diseases using mouse genetics and cell biology.