Mitochondrial malfunction perturbs lysosomal activities and cellular nutrient sensing pathways

线粒体功能障碍扰乱溶酶体活动和细胞营养传感途径

• 批准号: 10901047
• 负责人: Nuno Raimundo
• 金额: $ 41.85万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901047
• 关键词: 5' -AMP-activated protein kinase; Affect; Aging; Anabolism; Catabolism; Cell Aging; Cells; Cholesterol; Chronic; Communication; Cultured Cells; Data; Defect; Endoplasmic Reticulum; Folliculin; Goals; Homeostasis; Human; Impairment; In Vitro; Lysosomes; Mammals; Membrane; Metabolic; Metabolism; Mitochondria; Nutrient; Organelles; Paracrine Communication; Pathway interactions; Phenotype; Phospholipids; Phosphotransferases; Process; Repression; Residencies; Role; Signal Transduction; Site; Stress; Testing; Therapeutic Intervention; Work; cytokine; detection of nutrient; in vivo; intercellular communication; paracrine; phosphatidylinositol 3,5-diphosphate; pleiotropism; programs; proteostasis; recruit; response; senescence

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.

项目摘要 衰老的标志是众所周知的，包括线粒体功能障碍，营养感应失调， 改变细胞间通讯和衰老等。这些特征通常是 独立研究，目前还不清楚它们是如何协调的。对它的了解仍然很少，特别是在 哺乳动物，线粒体功能障碍如何与其他衰老标志相关。我们发现 线粒体功能障碍可影响溶酶体膜组成，这又影响溶酶体活性， 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 通过分泌细胞因子干扰营养感应和细胞间通讯， 衰老相关分泌表型（SASP）。值得注意的是，类似SASP的特征早在 衰老标志物，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老化标志， 细胞衰老的协调程序。 为了验证这一假设，我们将首先测试线粒体内容物如何被溶酶体感知， 这些内容的不同传递机制影响类似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，我们将测试溶酶体如何修饰 对线粒体功能障碍的反应导致异常的营养信号传导，以及这一特征如何进一步促进 SASP样签名和衰老，在体外和体内。最后，我们将测试 溶酶体膜组成影响溶酶体、线粒体和线粒体之间的物理接触位点。 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，我们将利用机制线粒体功能障碍和随之而来的溶酶体 损伤以协调的方式触发多种老化标志，通过提供窗口的机制， 治疗干预的机会。这些结果直接关系到更完整的理解 导致人类和其他哺乳动物细胞和有机体衰老的过程。