Roles of Mitochondrial Fusion in Optic Neuropathy

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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.