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.

抽象的 需要可视化我们周围的世界，感光体是有丝分裂后的视网膜神经元 必须保持健康和功能，以响应传入的光线。 感光体需要大量的能量，并且在各种应力​​源中都有鲁棒性 含有高活性氧和光辐射 线粒体会导致视力损失的破坏或竞争 线粒体动力学在应力中，产生了光感受器的寿命。 视觉疾病的疗法线粒体功能障碍首先需要了解 在压力和无重理条件下的线粒体动力学是理想的模型 有机体作为锥形感受器，包含一大堆位于该的线粒体 细胞体，响应整个24小时的能量需求 相应地生长或收缩。 突触或光感受器细胞的存在。 簇在压力条件下增加。 簇可能是保护光感受器的专门应力反应 光感受器的线粒体如何锚定或在此提案的目标中移动。 线粒体簇如何锚定在感光器中以及线粒体如何断裂 从群集和移动提示的突触。 观察到光感受器层和一部分光感受器Mitchondria共定位 与MüllerGlia。 绿色的点状在光感受器层内和外部表示线粒体周转 该提案的第2个，我将设计负责光感受器线粒体的细胞类型 失误。 MüllerGlia机械将要翻转的电池。 响应将洞悉光感受器如何保持稳健的时间 可以产生对视网膜疗法的见解，可以针对线粒体功能障碍 感受器。