Extracellular Matrix Control of Mitochondrial Homeostasis and Longevity

线粒体稳态和长寿的细胞外基质控制

基本信息

批准号：
10722664
负责人：
Andrew G Dillin
金额：
$ 38.73万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722664
关键词：
Address Aging Binding Caenorhabditis elegans Candidate Disease Gene Cell membrane Cell physiology Cells Cellular Stress Collagen Communication Data Disease Endoplasmic Reticulum Exhibits Extracellular Matrix Extracellular Matrix Degradation Fibroblasts Genes Genetic Genetic Models Genomic approach Global Change Glycoproteins Glycosaminoglycans Health Homeostasis Homologous Gene Human Hyaluronan Hyaluronic Acid Hyaluronidase Immune response Immunity Infection Inflammation Innate Immune Response Link Longevity Lysosomes Maintenance Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Metabolism Mitochondria Mitochondrial Matrix Modeling Molecular Mus Mutagenesis Natural Immunity Nematoda Nerve Degeneration Organelles Organism Oxidative Stress Paraquat Pathogenesis Pathogenicity Pathway interactions Physiological Play Process Proteins Quality Control Resistance Respiration Role Signal Pathway Signal Transduction Signaling Molecule Stress Testing Tissues Transforming Growth Factor beta Validation Vertebrates Virulence Factors age related biological adaptation to stress cell behavior endoplasmic reticulum stress follow-up functional decline functional genomics gene function host microbiome improved in vivo intercellular communication mitochondrial DNA mutation mitochondrial dysfunction novel overexpression pathogen pathogenic bacteria physical property protein folding proteostasis response tissue stress wound healing

项目摘要

PROJECT SUMMARY Maintenance of proper mitochondrial function is critical to organismal health. Mitochondrial stress contributes to ageing and the pathogenesis of numerous diseases. Intracellular insults, such as oxidative stress, mitochondrial DNA mutations, and disrupted interactions with other organelles including lysosomes and the endoplasmic reticulum are relatively well identified inducers of mitochondrial dysfunction. Yet it remains largely elusive how mitochondrial homeostasis can be altered upon changes in cellular microenvironment, the extracellular matrix (ECM). In mammals, ECM remodeling occurs during aging and in multiple diseases including infections, cancers, and neurodegeneration. The remodeled ECM may liberate bioactive fragments that can promote tissue damage- related responses, such as wound healing and inflammation. TMEM2 is a plasma membrane-bound hyaluronidase that cleaves hyaluronan, a major glycosaminoglycan constituent of the ECM in vertebrates. We discovered that TMEM2 induces mitochondrial stress responses in both human cells and nematodes, suggesting a novel conserved link between the ECM and mitochondria. In aim 1 and 2 of this proposal, we will systemically characterize TMEM2-induced global changes on mitochondria, determine what specific changes to the ECM are causative of these changes, and identify essential genetic regulators of the pathway in mammals and nematodes. Both aging and infection are associated with profound changes in the ECM. We observed that TMEM2 promotes longevity and immunity in nematodes, most likely due to changes to the ECM. We hypothesize that TMEM2- induced ECM degradation may be sensed as a signal of tissue damage mimicking infection or other environmental stress, which may elicit mitochondrial stress to potentiate mitochondrial stress responses and innate immune responses, and eventually prolong the lifespan due to these protective stress responses. In aim 3, we will test whether TMEM2-induced longevity is mediated by mitochondrial signaling, and whether the ECM- mitochondria signaling may be involved in immune responses during infection. Moreover, we will perform mass spectrometry as well as functional genomic screens to systemically assess the role of ECM remodeling in regulating mitochondrial homeostasis during aging.

项目摘要维持适当的线粒体功能对于有机体健康至关重要。线粒体应力有助于衰老和许多疾病的发病机理。细胞内损伤，例如氧化应激，线粒体 DNA突变，并破坏与包括溶酶体和内质的其他细胞器的相互作用网状功能障碍的网状识别诱导剂相对较好。然而，这在很大程度上难以捉摸在细胞微环境（细胞外基质）变化时，线粒体稳态可以改变（ECM）。在哺乳动物中，ECM重塑发生在衰老期间和多种疾病中，包括感染，癌症和神经变性。重塑的ECM可能会解放生物活性片段，以促进组织损害 - 相关反应，例如伤口愈合和炎症。 TMEM2是质膜结合的切割透明质酸的透明质酸酶是脊椎动物中ECM的主要糖胺聚糖成分。我们发现TMEM2在人类细胞和线虫中诱导线粒体应力反应，这表明 ECM和线粒体之间的一种新颖的保守联系。在本提案的目标1和2中，我们将系统地表征TMEM2诱导的线粒体上的全局变化，确定ECM的特定变化是什么这些变化的原因，并确定哺乳动物和线虫中途径的基本遗传调节剂。衰老和感染都与ECM的深刻变化有关。我们观察到TMEM2促进了线虫的寿命和免疫力，很可能是由于ECM的变化。我们假设TMEM2- 诱导的ECM降解可能被视为模仿感染或其他的组织损伤信号环境压力，可能引起线粒体应力以增强线粒体应力反应和天生的免疫反应，并由于这些保护性压力反应而最终延长了寿命。目标 3，我们将测试TMEM2诱导的寿命是否是由线粒体信号传导介导的，以及ECM-是否是通过线粒体信号传导可能参与感染过程中的免疫反应。而且，我们将进行质量光谱法和功能基因组筛选，以系统地评估ECM重塑在在衰老期间调节线粒体稳态。