Role of Mitochondrial Homeostasis in Animal Aging

项目摘要 由于高龄是阿尔茨海默病（AD）最重要的风险因素，因此针对有害的 与年龄相关的过程可能导致有效的治疗。线粒体功能障碍和促炎性 信号传导都被认为是衰老和AD的关键驱动因素。然而，一个清晰的认识， 线粒体稳态、免疫信号和衰老之间的联系仍然难以捉摸。线粒体 DNA（mtDNA）通常保存在线粒体内。然而，在线粒体应激或 损伤时，mtDNA可以释放到胞质溶胶中，从而遇到胞质溶胶DNA传感器并激活前体。 炎症反应。线粒体DNA在AD患者和细胞模型的脑中均有报道 但是，胞浆mtDNA是否可以靶向用于AD的治疗干预还没有被证实。 测定此外，关于胞质mtDNA在细胞内的发生和作用， 衰老和与年龄相关的健康下降。 在初步工作中，我们发现衰老导致线粒体自噬显著下降， 细胞质mtDNA的同时积累，这与不同器官中的促炎信号有关 果蝇的系统包括大脑。重要的是，我们发现成人发病，神经元特异性 沉默EYA（一种参与感受胞质DNA的分子）可抑制老年人的炎症信号传导 大脑和延长寿命。此外，我们还开发了减少胞浆mtDNA的遗传方法， 通过增加溶酶体DNA酶活性，在老年苍蝇。这些发现提供了重要的第一步， 理解细胞质mtDNA、免疫信号和健康之间的相互作用机制。 在这里，我们建议通过探索三个广泛的问题来建立这些突破性的发现： 1)线粒体内稳态、胞浆mtDNA和线粒体膜电位之间的机制关系是什么？ 衰老 2)胞质线粒体DNA和相关的促炎信号是否驱动衰老和与年龄相关的健康 下降？ 3)调节胞浆线粒体DNA和相关的促炎信号能对抗阿尔茨海默病吗 发病机理？ 本文所述的工作将为我们理解 衰老机制和AD相关病理学。我们的发现也可能导致新的治疗方法 对抗衰老、AD和相关痴呆症。

Project Summary As advanced age is the most significant risk factor for Alzheimer’s disease (AD), targeting detrimental age-related processes may lead to effective therapies. Mitochondrial dysfunction and pro-inflammatory signaling are each thought to be key drivers of aging and AD. However, a clear understanding of the connections between mitochondrial homeostasis, immune signaling and aging remains elusive. Mitochondrial DNA (mtDNA) is normally kept within the mitochondria. However, under conditions of mitochondrial stress or damage, mtDNA can be released into the cytosol thus encountering cytosolic DNA sensors and activating pro- inflammatory responses. Cytosolic mtDNA has been reported in the brains of AD patients and cellular models of AD, but, whether cytosolic mtDNA can be targeted for therapeutic intervention in AD has not been determined. Moreover, fundamental questions remain regarding the occurrence and role of cytosolic mtDNA in aging and age-related health decline. In preliminary work, we find that aging leads to a striking decline in mitochondrial autophagy and a concurrent accumulation of cytosolic mtDNA, which is linked to pro-inflammatory signaling in different organ systems of Drosophila including the brain. Critically, we have discovered that adult-onset, neuron-specific silencing of EYA, a molecule involved in sensing cytosolic DNA, dampens inflammatory signaling in the aged brain and extends lifespan. In addition, we have developed genetic approaches to reduce cytosolic mtDNA, via increased lysosomal DNase activity, in aged flies. These findings provide an important first step towards understanding the mechanistic interplay between cytosolic mtDNA, immune signaling and healthspan. Here, we propose to build upon these groundbreaking findings by exploring three broad questions: 1) What are the mechanistic relationships between mitochondrial homeostasis, cytosolic mtDNA, and aging? 2) Does cytosolic mtDNA and associated pro-inflammatory signaling drive aging and age-related health decline? 3) Can modulating cytosolic mtDNA and associated pro-inflammatory signaling counteract Alzheimer’s disease pathogenesis? The work described herein will bring about fundamental knowledge towards our understanding of the mechanisms of aging and AD-related pathology. Our findings may also lead to novel therapeutic approaches to counteract aging, AD and related dementias.