Autophagy and Mitochondrial Permeability in Aging and Longevity

衰老和长寿中的自噬和线粒体通透性

基本信息

批准号：
10688322
负责人：
ALEXANDER A SOUKAS
金额：
$ 34.44万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688322
关键词：
5&apos -AMP-activated protein kinase Aging Animals Autoimmune Autophagocytosis Biological Models Caenorhabditis elegans Cell physiology Cells Complex Data Defect Disease Eating Eukaryotic Cell FRAP1 gene Family Functional disorder Genes Genetic Genetic Transcription Glucocorticoids Goals Growth Growth Factor Health Health Promotion Human Inflammatory Intervention Lead Link Liver Longevity Mammals Metabolic Metabolism Mitochondria Molecular Morbidity - disease rate Mus Mutation Nerve Degeneration Neurodegenerative Disorders Organelles Organism Pathway interactions Permeability Phosphorylation Inhibition Phosphotransferases Predisposition Premature aging syndrome Process Protein Kinase Proteome Proteomics Public Health Regulation Reperfusion Injury Reporting Reproduction Research Resistance Serum Signal Pathway Signal Transduction Stress Testing Voltage-Dependent Anion Channel Work base combat genetic regulatory protein healthy aging human disease knockout animal liver ischemia loss of function mutation macromolecule mitochondrial permeability transition pore mutant neoplastic new therapeutic target next generation novel therapeutics prevent rational design therapeutic target

项目摘要

Autophagy is a conserved process by which all eukaryotic cells eliminate defective organelles and molecules, and is generally regarded as health- and longevity-promoting. 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 its regulation will permit us to target mitochondrial 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.

自噬是一个保守的过程，所有真核细胞都消除了有缺陷的细胞器和分子，通常被视为健康和长寿。自噬机械中的突变有助于对于自身免疫，代谢，炎症，肿瘤和神经退行性的人类状况疾病和迅速变化与过早衰老一致。相反，几乎所有遗传和延长寿命的环境操作以依赖自噬的方式进行。但是，我们已经确定自噬在情况下发生的自动噬对健康有负面影响线粒体渗透性增加。自噬在增加的情况下的净结果线粒体通透性缩短了寿命，并增加了对缺血/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调节渗透率，以开发下一代干预措施，以减少自噬在衰老和疾病中。该项目的长期目标是确定线粒体如何调节渗透率，并定义线粒体渗透性对细胞的后果和衰老的生物功能障碍。我们在此特定应用中的目标是定义上游的方式促进寿命和减少疾病抑制线粒体通透性涉及的信号通路，以及这对自噬，线粒体功能和寿命带来的后果。这个项目将满足这个通过研究调节线粒体通透性的详细机制，并该法规的后果。我们已经确定MTOR复合物2中信号的缺陷途径导致线粒体通透性和自噬的增加，缩短寿命和增加缺血/再灌注损伤。该提议的中心假设是低线粒体渗透性是一个自噬对寿命和衰老相关疾病的影响的中心决定因素。理由该建议是，更充分了解其法规将使我们能够针对线粒体的渗透性促进人类的健康衰老。在初步数据的指导下，我们将在三个特定的特定方面检验我们的假设目标。在AIM 1中，我们将定义线粒体通透性降低的机制 Prolongevity途径。在AIM 2中，我们将定义线粒体渗透性和 MTOR复合物2信号传导驱动自噬中的缺陷。 AIM 3将确定联盟的机制线粒体渗透性和自噬缩短寿命。这些研究结束时，我们将有确定了线粒体通透性破坏细胞功能并缩短的主要机制寿命。拟议的研究很重要，因为它将对理性设计具有广泛的影响下一代干预措施通过操纵自噬和线粒体渗透性。