Extracellular Matrix Control of Mitochondrial Homeostasis and Longevity

项目摘要 维持适当的线粒体功能对生物体健康至关重要。线粒体应激导致 衰老和许多疾病的发病机制。细胞内损伤，如氧化应激，线粒体损伤， DNA突变，并破坏与其他细胞器（包括溶酶体和内质网）的相互作用。 网织膜是线粒体功能障碍的相对较好鉴定的诱导物。然而，它仍然在很大程度上难以捉摸， 线粒体内稳态可以在细胞微环境，细胞外基质 （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、癌症和糖尿病。 神经变性重塑的ECM可以释放生物活性片段，其可以促进组织损伤- 相关反应，如伤口愈合和炎症。TMEM 2是一种质膜结合的 切割透明质酸的透明质酸酶，透明质酸是脊椎动物ECM的主要糖胺聚糖成分。我们 发现TMEM 2在人类细胞和线虫中都诱导线粒体应激反应，这表明 ECM和线粒体之间的一种新的保守联系。在本提案的目标1和2中，我们将系统地 表征TMEM 2诱导的线粒体整体变化，确定ECM的具体变化 这些变化的原因，并确定在哺乳动物和线虫途径的基本遗传调节。 衰老和感染都与ECM的深刻变化有关。我们观察到TMEM 2促进了 线虫的寿命和免疫力，最有可能是由于ECM的变化。我们假设TMEM 2- 诱导的ECM降解可被感测为模拟感染或其它组织损伤的信号 环境应激，其可引起线粒体应激以增强线粒体应激反应， 先天免疫反应，并最终延长寿命，由于这些保护性的应激反应。在aim中 3，我们将测试TMEM 2诱导的寿命是否是由线粒体信号传导介导的，以及ECM-2是否是由线粒体信号传导介导的。 线粒体信号传导可能参与感染期间的免疫应答。此外，我们将执行质量 光谱以及功能基因组筛选，以系统地评估ECM重塑在 在衰老过程中调节线粒体内稳态。

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.