Regulation of autophagy and mitochondrial permeability by target of rapamycin complex 2

自噬是所有真核细胞清除有缺陷的细胞器和分子的保守过程， 通常被认为是一个促进健康和长寿的过程。自噬机制中的突变 有助于人类疾病，如自身免疫、新陈代谢、炎症、肿瘤和 神经退行性疾病，并与过早衰老相一致的迅速变化。相反，几乎所有的 延长寿命的基因和环境操作是以一种依赖于自噬的方式实现的。 然而，我们已经确定，当自噬发生在 线粒体通透性增加的设定。在增加的环境中自噬的净后果 线粒体通透性缩短了寿命，增加了对缺血/再灌注损伤的敏感性。 迫切需要了解线粒体的细胞和分子机制 控制渗透率是为了开发下一代干预措施，以减少 衰老和疾病中的自噬。这个项目的长期目标是确定线粒体如何 通透性被调节，并确定线粒体通透性增加对细胞的影响 以及衰老过程中的器官功能障碍。我们在此特定应用程序中的目标是定义上游 促进长寿和减少疾病的信号通路抑制线粒体通透性， 以及这对自噬、线粒体功能和寿命的影响。本项目将满足这一要求 目的通过研究线粒体通透性调节的详细机制，探讨线粒体通透性的调节机制。 这一规定的后果。我们已经确定mTOR复合体2中的信号缺陷 途径导致线粒体通透性和自噬增加，缩短寿命和增加 缺血/再灌注损伤。这一建议的中心假设是低线粒体通透性是一种 自噬对寿命和衰老相关疾病影响的中心决定因素。其基本原理是 这一建议是，更全面地了解线粒体通透性的调节将使我们能够 促进人体健康衰老的渗透性。在初步数据的指导下，我们将在 三个具体目标。在目标1中，我们将定义线粒体通透性降低的机制 通过延长寿命的途径。在目标2中，我们将定义线粒体通透性和 MTOR复合体2信号转导缺陷导致自噬。目标3将决定联合的机制 线粒体通透性和自噬会缩短寿命。在这些研究结束后，我们将拥有 确定了线粒体通透性扰乱细胞功能和缩短的主要机制 寿命。这项拟议的研究具有重要意义，因为它将对城市道路的合理设计产生广泛的影响 通过操纵自噬和促进健康衰老的下一代干预 线粒体通透性。

Autophagy is a conserved process by which all eukaryotic cells eliminate defective organelles and molecules, and is generally regarded as a health- and longevity-promoting process. Mutations in the autophagy machinery contribute to human conditions such as autoimmune, metabolic, inflammatory, neoplastic, and neurodegenerative diseases, and prompt changes consistent with premature aging. Conversely, nearly all genetic and environmental manipulations that extend lifespan do so in a manner dependent upon autophagy. However, we have determined that autophagy has negative consequences on health when it occurs in the setting of increased mitochondrial permeability. The net consequence of autophagy in the setting of increased mitochondrial permeability is shortened lifespan and increased susceptibility to ischemia/reperfusion injury. There is a critical need to understand the cellular and molecular mechanisms by which mitochondrial permeability is regulated in order to develop the next generation of interventions to reduce negative impacts of autophagy in aging and disease. The long-term goal of this project is to determine how mitochondrial permeability is regulated and to define the consequences of increased mitochondrial permeability on cellular and organismal dysfunction in aging. Our objective in this particular application is to define how upstream signaling pathways involved in promoting longevity and reducing disease suppress mitochondrial permeability, and the consequences this has on autophagy, mitochondrial function, and lifespan. This project will meet this objective by studying the detailed mechanisms by which mitochondrial permeability is regulated and the consequences of this regulation. We have determined that defects in signaling in the mTOR complex 2 pathway lead to increases in mitochondrial permeability and autophagy, shortening lifespan and increasing ischemia/reperfusion injury. The central hypothesis of this proposal is that low mitochondrial permeability is a central determinant of the effects of autophagy on lifespan and aging-associated diseases. The rationale for this proposal is that fuller understanding of the regulation of mitochondrial permeability will permit us to target permeability to promote healthy aging in humans. Guided by preliminary data, we will test our hypothesis in three specific aims. In Aim 1, we will define the mechanisms by which mitochondrial permeability is decreased by prolongevity pathways. In Aim 2 we will define the mechanisms by which mitochondrial permeability and defects in mTOR complex 2 signaling drive autophagy. Aim 3 will determine the mechanism by which the union of mitochondrial permeability and autophagy shorten lifespan. At the conclusion of these studies, we will have identified the major mechanisms by which mitochondrial permeability disrupts cellular function and shortens lifespan. The proposed research is significant because it will have broad implications for rational design of the next generation of interventions that promote healthy aging through manipulation of autophagy and mitochondrial permeability.