Mitochondrial malfunction perturbs lysosomal activities and cellular nutrient sensing pathways

项目总结 衰老的特征是公认的，包括线粒体功能障碍，放松营养感知， 改变了细胞间的通讯，以及衰老等。这些特征通常是 独立学习，目前还不清楚它们是如何协调的。它仍然鲜为人知，特别是在 哺乳动物，线粒体功能障碍如何与衰老的其他特征相关联。我们发现， 线粒体功能障碍会影响溶酶体膜成分，进而影响溶酶体的活性， 我们的初步数据显示，线粒体功能障碍和溶酶体损伤的综合作用 通过分泌类似于细胞因子的细胞因子干扰营养感知和细胞间通讯 衰老相关分泌表型(SASP)。值得注意的是，类似SASP的签名很久以前就可以检测到 衰老的标志，并且是完全可逆的。因此，我们假设线粒体功能障碍及其 对线粒体-溶酶体串扰的影响可以触发其他细胞衰老的特征，从而释放 细胞老化的协调计划。 为了验证这一假设，我们将首先测试线粒体内容如何被溶酶体感知，以及如何 这些内容的不同交付机制会影响类似SASP的签名。然后我们将测试 SASP样信号通过旁分泌信号触发衰老。接下来，我们将测试溶酶体是如何在 对线粒体故障的反应会导致营养信号的异常，以及这一特征是如何进一步发挥作用的 对SASP样信号和衰老的影响，无论是在体外还是体内。最后，我们将测试 溶酶体膜成分影响溶酶体、线粒体和线粒体之间的物理接触部位 内质网，以及这种细胞器重排如何有助于衰老表型。 通过这项工作，我们将利用线粒体功能障碍和随后的溶酶体的机制 损伤通过提供窗口的机制以协调的方式触发多个老化特征 治疗干预的机会。这些结果与更完整的理解有直接关系 导致人类和其他哺乳动物细胞和组织衰老的过程。

PROJECT SUMMARY The hallmarks of aging are well established, and include mitochondrial malfunction, deregulated nutrient sensing, altered inter-cellular communication, and senescence, among others. These hallmarks have typically been studied independently, and it is unclear how they are coordinated. It remains poorly understood, particularly in mammals, how mitochondrial malfunction relates with the other hallmarks of aging. We have found that mitochondrial malfunction can affect lysosomal membrane composition, which in turn impacts lysosomal activity, and our preliminary data show that the combined effect of mitochondrial malfunction and lysosomal impairment perturbs nutrient sensing and inter-cellular communication through the secretion of cytokines akin to the senescence-associated secretory phenotype (SASP). Notably, the SASP-like signature is detectable long before senescence markers and is fully reversible. Therefore, we hypothesize that mitochondrial malfunction and its impact on mitochondria-lysosome crosstalk can trigger other cellular aging hallmarks thus unleashing a coordinated program of cellular aging. To test this hypothesis, we will first test how mitochondrial contents can be sensed by the lysosomes, and how different mechanisms of delivery of those contents impact the SASP-like signature. We will then test how the SASP-like signature triggers senescence via paracrine signaling. Next, we will test how lysosomes modified in response to mitochondrial malfunction cause aberrant nutrient signaling, and how this feature further contributes to SASP-like signature and senescence, both in vitro and in vivo. Finally, we will test how the changes in lysosomal membrane composition affect the physical contact sites between lysosomes, mitochondria and endoplasmic reticulum, and how this organelle rearrangement contributes to the aging phenotypes. Through this work, we will harness the mechanisms mitochondrial malfunction and the consequent lysosomal impairment trigger multiple aging hallmarks in a coordinated manner, through mechanisms that provide a window of opportunity for therapeutic interventions. These results are directly relevant to a more complete understanding of the processes leading to cellular and organismal aging in humans and other mammals.