Mitochondrial function and dysfunction in hair cells

项目总结 影响线粒体功能的30多个基因的遗传中断会导致听力损失。我们建议 了解机械感觉毛细胞中典型突变的细胞后果。我们的 初步研究表明，毛细胞在成熟时会经历快速的线粒体生物生成，并且 线粒体会主动对机械感觉信号做出反应。我们建议进行研究，以了解这一规定 线粒体的生长和功能，重点是线粒体之间的特殊连接的作用 内质网(ER)。越来越多的证据支持内质网-线粒体连接的作用 调节线粒体新陈代谢、动力学和应激，并在调节细胞死亡中发挥中心作用。 我们建议使用斑马鱼侧线毛细胞的实时成像进行实验，该系统适用于 活体细胞功能的研究。我们将评估头发中线粒体的生长、氧化和ATP的利用 细胞，并确定干扰内质网-线粒体通讯的后果。我们将衡量 线粒体对机械刺激的反应变化。使用CRISPR，我们将产生斑马鱼 评估毛细胞功能后果的人类线粒体突变模型。我们的实验 将揭示毛细胞中线粒体的潜在基本机制以及这些机制是如何进行的 人类听力丧失的错误。

PROJECT SUMMARY Genetic disruptions of over thirty genes affecting mitochondrial functions result in hearing loss. We propose to understand the cellular consequences of representative mutations in mechanosensory hair cells. Our preliminary studies demonstrate that hair cells undergo rapid mitochondrial biogenesis as they mature, and that mitochondria actively respond to mechanosensory cues. We propose studies to understand the regulation of mitochondrial growth and function, focusing on the roles of specialized connections between mitochondria and the endoplasmic reticulum (ER). Growing evidence supports a role for ER-mitochondrial junctions regulating mitochondrial metabolism, dynamics, and stress and for playing a central role in regulated cell death. We propose experiments using live imaging of hair cells in the zebrafish lateral line, a system amenable to study of cellular functions in vivo. We will assess mitochondrial growth, oxidation and ATP utilization in hair cells, and determine the consequences of disrupting ER-mitochondrial communication. We will measure changes in mitochondria in response to mechanical stimuli. Using CRISPR, we will generate zebrafish models of human mitochondrial mutations to assess functional consequences for hair cells. Our experiments will reveal potentially fundamental mechanisms of mitochondria in hair cells and how these mechanisms go awry in human hearing loss.