Targeting ER-mitochondrial calcium signaling to promote healthier aging

靶向 ER 线粒体钙信号传导以促进更健康的衰老

• 批准号: 10643969
• 负责人: Kristopher Burkewitz
• 金额: $ 32.49万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643969
• 关键词: Age of Onset; Aging; Alzheimer' s Disease; Anatomy; Animals; Behavior; Bioenergetics; Biological; Caenorhabditis elegans; Calcium; Calcium Signaling; Cardiovascular Diseases; Cells; Communication; Complex; Coupled; Data; Defect; Diabetes Mellitus; Disease; Electron Transport; Endoplasmic Reticulum; Engineering; Foundations; Functional disorder; Gene Expression; Genetic; Goals; Health; Homeostasis; Impairment; Inositol; Intervention; Lead; Life; Link; Longevity; Longevity Pathway; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mediator; Membrane; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Morphology; Neurons; Onset of illness; Organelles; Pathology; Pathway interactions; Physiological; Porifera; Process; Proteomics; Public Health; Regulation; Role; Rough endoplasmic reticulum; Shapes; Signal Transduction; Site; Structure; Study models; Testing; Tissues; Work; age related; aged; cell type; experimental study; genetic analysis; genetic manipulation; healthspan; mitochondrial dysfunction; mitochondrial fitness; mutant; novel; novel strategies; novel therapeutic intervention; novel therapeutics; receptor; receptor function; release of sequestered calcium ion into cytoplasm; spatiotemporal; therapeutic target; tripolyphosphate

Project Summary/Abstract Fundamental gaps remain in our understanding of the cell biological mechanisms that drive mitochondrial decline and associated age-related diseases. Organelles like the mitochondria and endoplasmic reticulum (ER) are physically and functionally linked, in part via sites of membrane contact. These lines of communication between mitochondria and other organelles represent an understudied avenue by which to therapeutically target mitochondrial function. Our long-term goal is to understand the physiological roles of inter-organelle communication during aging and age-related disease. In pursuit of that goal, our objective in this application is to determine how the ER regulates mitochondrial health during aging through its role as a platform for calcium signaling. We have exploited the simple anatomy of C. elegans and experimental advantages in genetics and microscopy to lay a foundation in this model for the study of ER-mitochondrial interactions. Similar to mammals, the worm ER calcium efflux channel, inositol triphosphate receptor (InsP3R), exerts potent control over mitochondrial bioenergetics, and we have extended the roles of InsP3R to regulation of mitochondrial gene expression and dynamics in the worm as well. Furthermore, the InsP3R regulates lifespan in C. elegans through mechanisms that depend upon mitochondrial function. Here we will test the hypothesis that ER remodeling in aging animals acts to trigger mitochondrial dysfunction and organismal decline by promoting aberrant subcellular calcium signaling and dynamics. To test this hypothesis, we will first determine whether the InsP3R is a cell autonomous regulator of mitochondrial function and lifespan. Secondly, we will identify the molecular mechanisms linking InsP3R activity to the diverse changes observed in mitochondrial behavior. Finally, we will determine how organellar remodeling of the calcium flux machineries initiates age-onset mitochondrial dysfunction. By revealing the mechanisms by which ER signaling governs mitochondrial health at the organismal level, these results will open new therapeutic avenues in treating mitochondrial pathologies.

项目摘要/摘要 在我们对导致线粒体衰退的细胞生物学机制的理解上仍然存在根本的差距 以及与年龄相关的疾病。线粒体和内质网(ER)等细胞器 物理上和功能上相连，部分通过膜接触部位。这些通信线路之间 线粒体和其他细胞器是一种尚未被研究的治疗靶向途径。 线粒体功能。我们的长期目标是了解细胞器间的生理作用。 衰老过程中的沟通和与年龄相关的疾病。为了实现这一目标，我们在此应用程序中的目标是 确定内质网如何通过其作为钙平台的作用调节线粒体在衰老过程中的健康 发信号。我们利用线虫的简单解剖和实验优势，在遗传学和 为进一步研究内质网-线粒体的相互作用奠定了基础。与哺乳动物相似， 蠕虫的内质网钙外流通道，三磷酸肌醇受体(InsP3R)，对 线粒体生物能量学，我们已经将InsP3R的作用扩展到线粒体基因的调控 在蠕虫中的表达和动力学也是如此。此外，InsP3R通过以下途径调节线虫的寿命 依赖于线粒体功能的机制。在这里，我们将检验这一假设，即ER重塑在 衰老的动物通过促进异常的亚细胞而引发线粒体功能障碍和机体衰退 钙信号和动力学。为了验证这一假设，我们将首先确定InsP3R是否是一个细胞 线粒体功能和寿命的自主调节。其次，我们将对分子进行鉴定 将InsP3R活性与观察到的线粒体行为的不同变化联系起来的机制。最后，我们会 确定钙流机制的细胞器重塑如何启动老年性线粒体 功能障碍。通过揭示ER信号调控生物线粒体健康的机制 这些结果将为治疗线粒体病变开辟新的治疗途径。