Mitochondrial Stress Signal Transduction from Organelle to Organism

从细胞器到生物体的线粒体应激信号转导

• 批准号: 9488035
• 负责人: Martin Picard
• 金额: $ 32.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9488035
• 关键词: Animal Model; Antioxidants; Biochemical; Biological Assay; Cell Nucleus; Cell model; Communication; Coupled; Defect; Disease; Disease model; Drug usage; Electron Microscopy; Follow-Up Studies; Foundations; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Human; Human Genome; Laboratories; Metabolic; Mitochondria; Mitochondrial DNA; Morphology; Muscle Cells; Neurosecretory Systems; Nuclear; Organelles; Organism; Pathway interactions; Pattern; Pharmacology; Resolution; Role; Signal Pathway; Signal Transduction; Stress; System; Technology; Testing; Work; experimental study; genetic manipulation; human disease; light microscopy; metabolomics; mitochondrial dysfunction; novel; programs; response; small molecule; stressor; transcriptomics

PROJECT SUMMARY Neuroendocrine and metabolic stressors threaten cellular and organismal integrity, leading to maladaptive cellular changes and disease unless met by adaptive remodeling of nuclear gene expression. Mitochondria are central to these adaptations. Recent findings indicate that mitochondria participate in a three- step intracellular signal transduction system involving sensing, signal integration and transduction to the nucleus where they regulate the majority of genes within the human genome. In this way, mitochondria are a emerging as determinants of cellular and organismal adaptation to common stressors. The overall objective of this proposal is to define novel mechanisms of mitochondria-mitochondria and mitochondria-nuclear signaling leading to gene expression remodeling. To achieve this, my laboratory uses use drug-inducible inter-organellar linker technology to manipulate mito-mito and mito-nuclear interactions in muscle cells, coupled to high-resolution quantitative light and electron microscopy approaches to track organelle interactions. We exploit high-throughput functional assays, metabolomics, and transcriptomics to visualize and understand the resulting nuclear transcriptional responses patterns to stressors. To disentangle the relative contributions of mitochondrial network organization and functions to mitochondrial signaling, we leverage unique trans-mitochondrial cell and animal models, as well as mitochondria-targeted small molecule antioxidants and pharmacological agents. Candidate signaling pathways will be validated using parallel genetic and biochemical experiments. Most promising pathways will be extended in follow up studies using a near- experimental human disease model of primary mitochondrial DNA defects to validate our findings in humans. Together, this combined approach will investigate specific components of the mitochondria-nuclear communication system and their relevance to human disease. This work will establish the physical basis for gene expression regulation by mitochondria, and serve as the foundation for further work aiming to circumvent maldaptative cellular and organismal responses to stressors and mitochondrial dysfunction.

项目摘要 神经内分泌和代谢压力源威胁性细胞和生物完整性，导致 除非通过适应性重塑核基因表达来满足不良的细胞变化和疾病。 线粒体对于这些适应至关重要。最近的发现表明，线粒体参与了三个 步进细胞内信号转导系统，涉及传感，信号积分和转导向 它们调节人基因组中大多数基因的核。这样，线粒体是 作为对普通压力源的细胞和生物适应的决定因素。 该提议的总体目的是定义线粒体线粒体和 线粒体核信号传导导致基因表达重塑。为了实现这一目标，我的实验室使用 使用药物诱导的跨加工链接器技术来操纵MITO-MITO和MITO-核互动 肌肉细胞，结合高分辨率的定量光和电子显微镜方法跟踪 细胞器相互作用。我们利用高通量功能测定，代谢组学和转录组学 可视化并了解对压力源的核转录响应模式。解开 线粒体网络组织和功能对线粒体信号的相对贡献，我们 利用独特的反式线粒体细胞和动物模型，以及靶向线粒体的小分子 抗氧化剂和药理学剂。候选信号通路将使用平行遗传来验证 和生化实验。最有前途的途径将在后续研究中扩展 原发性线粒体DNA缺陷的实验人类疾病模型，以验证我们在人类中的发现。 共同的方法将研究线粒体核的特定组成部分 沟通系统及其与人类疾病的相关性。这项工作将建立物理基础 通过线粒体调节基因表达调节，并作为旨在规避的进一步工作的基础 对压力源和线粒体功能障碍的马尔多斯细胞和生物反应。