Understanding mitochondrial movement and turnover in stressed and unstressed photoreceptors

了解应激和非应激光感受器中的线粒体运动和周转

• 批准号: 10461549
• 负责人: Kaitlyn Michelle Rutter
• 金额: $ 4.12万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461549
• 关键词: Actins; Animal Model; Autophagocytosis; Autophagosome; Blindness; Cells; Cessation of life; Chronic stress; Color; Cone; Cytoskeleton; Degradation Pathway; Health; Hour; Image; Impairment; Label; Larva; Lead; Light; Longevity; LysoTracker; Lysosomes; Maintenance; Metabolic; Microtubules; Mitochondria; Mitochondrial Matrix; Mitotic; Modeling; Monitor; Movement; Muller' s cell; Organelles; Photoreceptors; Process; Quality Control; Radiation; Reactive Oxygen Species; Retina; Retinal Cone; Retinal Diseases; Retinal Photoreceptors; Stress; Synapses; Testing; Time; Transgenic Organisms; Tubulin; Vision; Vision Disorders; Zebrafish; base; biological adaptation to stress; cell type; cold stress; experimental study; fluorophore; inhibitor; insight; mitochondrial dysfunction; new therapeutic target; novel; promoter; response; retinal neuron; stressor; therapy development

ABSTRACT Required to visualize the world around us, photoreceptors are post-mitotic retinal neurons that must remain healthy and functional to respond to incoming light. Throughout a lifetime, photoreceptors require high amounts of energy and are robust amongst various stressors including high reactive oxygen species and light radiation. Dysfunctional photoreceptor mitochondria can lead to disrupted or complete vision loss. Uncovering mechanisms supporting mitochondrial dynamics during stress will yield insight into photoreceptor longevity. Developing therapies for visual disorders involving mitochondrial dysfunction first requires an understanding of mitochondrial dynamics in stressed and unstressed conditions. Zebrafish are ideal model organisms as their cone photoreceptors contain a large cluster of mitochondria localized to the cell body. In response to energy demands throughout the 24-hour day, the mitochondrial cluster grows or shrinks accordingly. Rarely mitochondria move away from this cluster towards the synapse or outside the photoreceptor cell. The presence of mitochondria localized away from the cluster is increased in stressed conditions. Moving unhealthy mitochondria away from the healthy cluster may be a specialized stress response to protect photoreceptors. It is currently unknown how photoreceptor mitochondria are anchored or move. In aim 1 of this proposal, I will uncover how the mitochondrial cluster is anchored in photoreceptors and how mitochondria can break free from that cluster and move towards the synapse. Photoreceptor mitochondria have been observed outside the photoreceptor layer and a portion of photoreceptor mitochondria colocalized with Müller glia. Some ‘mislocalized’ photoreceptor mitochondria colocalized with Lysotracker Green puncta within and outside the photoreceptor layer indicating mitochondrial turnover. In aim 2 of this proposal, I will determine the cell type(s) responsible for photoreceptor mitochondrial turnover. I predict that unhealthy mitochondria are separated from the cluster and ejected from the cell to be turned over by Müller glia machinery. Understanding the mechanisms of this stress response will give insight into how photoreceptors remain robust throughout time. These findings can yield insights into how retinal therapies can target mitochondrial dysfunction in photoreceptors.

摘要 光感受器是视觉化我们周围世界所必需的，是有丝分裂后的视网膜神经元 必须保持健康和功能，以便对入射光线做出反应。在一生中， 光感受器需要很高的能量，并且在各种应激源中都很健壮 包括高活性氧基团和光辐射。光感受器功能障碍 线粒体可能会导致失明或完全失明。揭示支撑机制 线粒体在应激过程中的动态变化将有助于了解光感受器的寿命。发展中 涉及线粒体功能障碍的视力障碍的治疗首先需要了解 在应激和非应激条件下的线粒体动力学。斑马鱼是理想的模式 生物体作为其锥形感光器，包含一大簇定位于 细胞体。为了应对全天24小时的能量需求，线粒体簇 相应地增长或缩小。线粒体很少离开这一簇而移动到 突触或光感受器细胞外。线粒体的存在定位于远离大脑的 在应激条件下，团簇增加。将不健康的线粒体从健康的线粒体中移开 簇可能是保护光感受器的一种特殊的应激反应。目前还不清楚 光感受器线粒体是如何锚定或移动的。在这项提案的目标1中，我将揭示 线粒体簇如何锚定在光感受器中，以及线粒体如何解脱 并向突触移动。光感受器线粒体已经被 光感受器层外观察与部分光感受器线粒体共定位 和米勒·格里亚。一些错位的光感受器线粒体与Lysotracker共定位 光感受器层内外的绿色斑点，表示线粒体的更替。在AIM 在这项建议中，我将确定负责光感受器线粒体的细胞类型(S 营业额。我预测不健康的线粒体会从星团中分离出来并从 将由Müler Glia机械翻转的单元格。了解这种应激反应的机制 这一反应将让我们深入了解光感受器是如何在一段时间内保持强健的。这些发现 可以深入了解视网膜疗法如何针对线粒体功能障碍 光感受器。