Regulation of mitochondrial homeostasis through retrograde signaling

通过逆行信号调节线粒体稳态

• 批准号: 10133090
• 负责人: VALENTINA PERISSI
• 金额: $ 43.83万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133090
• 关键词: 3T3-L1 Cells; Address; Adipocytes; Apoptotic; Binding; Biochemical; Biogenesis; Caenorhabditis elegans; Cell Lineage; Cell Nucleus; Cells; Cellular Metabolic Process; Chromatin; Communication; Cues; Data; Defect; Development; Disease; Epigenetic Process; Equilibrium; Eukaryotic Cell; Excision; GPS2 gene; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Hela Cells; Histones; Homeostasis; Homologous Gene; Insulin Resistance; Lead; Maintenance; Mammalian Cell; Mammals; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Molecular; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Nutritional; Pathway interactions; Personal Satisfaction; Play; Proteomics; Regulation; Role; Signal Pathway; Signal Transduction; Stress; Structural Models; Techniques; Transcriptional Activation; Translating; Ubiquitin-Conjugating Enzymes; Ubiquitination; Yeasts; activating transcription factor 1; base; cell type; cofactor; common cellular transcription factor ATF; experimental study; flexibility; genome-wide; global run on sequencing; human disease; inhibitor/antagonist; mitochondrial dysfunction; novel; prevent; programs; promoter; recruit; response; sensor; therapeutic target; transcriptome sequencing

PROJECT SUMMARY / ABSTRACT Because the majority of mitochondrial proteins are encoded in the nuclear genome, mitochondrial biogenesis and maintenance of mitochondrial homeostasis ultimately depend on nuclear transcription being regulated in response to mitochondrial damage and to changes in cell metabolism or nutrients availability. However, the pathways controlling mitochondria-to-nucleus communication in mammalian cells are still largely unknown. Here, we propose to investigate the hypothesis that the transcriptional cofactor GPS2 regulates mitochondrial homeostasis as a direct mediator of mitochondrial retrograde signaling in mammalian cells with the following Aims: i) Characterize the role of GPS2 in promoting transcriptional activation of nuclear-encoded mitochondrial genes; ii) Dissect the regulation of GPS2 shuttling between mitochondria and nucleus and define the gene programs regulated upon translocation; iii) Elucidate the role of GPS2 retrograde translocation in regulating mitochondrial homeostasis. To achieve these goals, we will use a combination of biochemical techniques, genome wide ChIPseq/RNAseq experiments and open-ended proteomic approaches to dissect the molecular mechanism underlying GPS2-mediated regulation of mitochondrial gene expression in the nucleus and elucidate the regulatory strategies that control GPS2 retrograde translocation both in conditions of mitochondrial stress and during the differentiation of specialized cell lineages. Overall, successful completion of the studies outlined in this application will: 1) identify a novel player in the regulation of mitochondrial gene expression and elucidate the molecular mechanism of its transcriptional activity, 2) dissect the first direct pathway of mitochondrial retrograde signaling in mammalian cells, and 3) reveal an unexpected regulatory strategy for integrating stress and metabolic signaling within the cell through inhibition of non-proteolytic ubiquitination.

项目摘要 /摘要 因为大多数线粒体蛋白是在核基因组中编码的，所以 线粒体生物发生和线粒体稳态的维持最终 取决于响应线粒体损伤的核转录 以及细胞代谢或营养可用性的变化。但是，路径 在哺乳动物细胞中控制线粒体到核的通信仍然很大程度上是 未知。在这里，我们建议研究转录的假设 辅因子GPS2调节线粒体稳态为直接调解器 哺乳动物细胞中的线粒体逆行信号传导以下目的：i） 表征GPS2在促进核编码的转录激活中的作用 线粒体基因； ii）剖析线粒体之间的GPS2穿梭的调节 细胞核和定义在易位时调节的基因程序； iii）阐明 GPS2逆行易位在调节线粒体稳态中的作用。到 实现这些目标，我们将结合生化技术，基因组广泛 chipseq/rnaseq实验和开放式蛋白质组学方法剖析 GPS2介导的线粒体基因调节的分子机制 在细胞核中的表达并阐明控制GPS2的调节策略 在线粒体应力的条件下以及在 专门细胞谱系的分化。总体而言，成功完成研究 该应用程序中概述的将：1）确定线粒体调节中的新型玩家 基因表达并阐明其转录活性的分子机制，2） 剖析哺乳动物细胞中线粒体逆行信号的第一个直接途径， 3）揭示了一个意外的调节策略，用于整合压力和代谢 通过抑制非蛋白水解泛素化的信号传导。

项目成果

Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling.

• DOI: 10.3389/fcell.2020.608044
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Chan S;Smith E;Gao Y;Kwan J;Blum BC;Tilston-Lunel AM;Turcinovic I;Varelas X;Cardamone MD;Monti S;Emili A;Perissi V
• 通讯作者: Perissi V

Interaction between poly(A)-binding protein PABPC4 and nuclear receptor corepressor NCoR1 modulates a metabolic stress response.

• DOI: 10.1016/j.jbc.2023.104702
• 发表时间: 2023-06
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Oliveira, A G;Oliveira, L D;Cruz, M V;Guimaraes, D S P S F;Lima, T I;Santos-Favero, B C;Luchessi, A D;Pauletti, B A;Leme, A P;Bajgelman, M C;Afonso, J;Regitano, L C A;Carvalho, H F;Carneiro, E M;Kobarg, J;Perissi, V;Auwerx, J;Silveira, L R
• 通讯作者: Silveira, L R