Extracellular Matrix Control of Mitochondrial Homeostasis and Longevity

项目总结 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 衰老与多种疾病的发病机制。细胞内的伤害，如氧化应激，线粒体 DNA突变，并破坏与其他细胞器的相互作用，包括溶酶体和内质 网状结构是线粒体功能障碍的诱因。然而，它在很大程度上仍然难以捉摸 线粒体的动态平衡可以随着细胞微环境、细胞外基质的改变而改变 (ECM)。 在哺乳动物中，细胞外基质重塑发生在衰老和多种疾病中，包括感染、癌症和 神经退行性变。改装后的ECM可能会释放出生物活性碎片，从而促进组织损伤- 相关反应，如伤口愈合和炎症。TMEM2是一种质膜结合的分子 透明质酸分解透明质酸的酶，透明质酸是脊椎动物细胞外基质中的一种主要糖胺聚糖成分。我们 发现TMEM2在人类细胞和线虫中都能诱导线粒体应激反应，提示 细胞外基质和线粒体之间的一种新的保守联系。在本提案的目标1和目标2中，我们将系统地 描述TMEM2诱导的线粒体全局变化，确定ECM的具体变化是什么 这些变化的起因，并确定哺乳动物和线虫中该途径的基本遗传调节因子。 衰老和感染都与细胞外基质的深刻变化有关。我们观察到TMEM2促进 线虫的寿命和免疫力，很可能是由于细胞外基质的变化。我们假设TMEM2- 诱导的细胞外基质降解可被感知为组织损伤的信号，模仿感染或其他 环境应激，可诱导线粒体应激，以增强线粒体应激反应，并 先天免疫反应，并最终由于这些保护性应激反应而延长寿命。在AIM 3，我们将测试TMEM2是否通过线粒体信号介导诱导长寿，以及ECM是否- 线粒体信号可能参与了感染过程中的免疫反应。此外，我们还将进行弥撒 光谱分析和功能基因组筛选，系统地评估细胞外基质重塑在 调节衰老过程中线粒体的动态平衡。

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.