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: 9925788
• 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/9925788
• 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.

项目总结

项目成果

3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus.

• DOI: 10.1016/j.celrep.2021.109509
• 发表时间: 2021-08-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Faitg J;Lacefield C;Davey T;White K;Laws R;Kosmidis S;Reeve AK;Kandel ER;Vincent AE;Picard M
• 通讯作者: Picard M

Multilevel heterogeneity of mitochondrial respiratory chain deficiency.

线粒体呼吸链缺陷的多级异质性。

• DOI: 10.1002/path.5146
• 发表时间: 2018
• 期刊: The Journal of pathology
• 作者: Vincent,AmyE;Picard,Martin
• 通讯作者: Picard,Martin

The social nature of mitochondria: Implications for human health.

• DOI: 10.1016/j.neubiorev.2020.04.017
• 发表时间: 2021-01
• 期刊: Neuroscience and biobehavioral reviews
• 影响因子: 8.2
• 作者: Picard M;Sandi C
• 通讯作者: Sandi C

Mitochondrial DNA, nuclear context, and the risk for carcinogenesis.

• DOI: 10.1002/em.22169
• 发表时间: 2019-06
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Kaufman BA;Picard M;Sondheimer N
• 通讯作者: Sondheimer N

Quantitative 3D Mapping of the Human Skeletal Muscle Mitochondrial Network.

人类骨骼肌线粒体网络的定量 3D 绘图。

• DOI: 10.1016/j.celrep.2019.03.051
• 发表时间: 2019
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Vincent,AmyE;White,Kathryn;Davey,Tracey;Philips,Jonathan;Ogden,RTodd;Lawless,Conor;Warren,Charlotte;Hall,MattG;Ng,YiShiau;Falkous,Gavin;Holden,Thomas;Deehan,David;Taylor,RobertW;Turnbull,DougM;Picard,Martin
• 通讯作者: Picard,Martin