The role of sub-lethal mitochondrial apoptotic stress in cellular senescence

亚致死线粒体凋亡应激在细胞衰老中的作用

• 批准号: 10026558
• 负责人: Joao Passos
• 金额: $ 43.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10026558
• 关键词: Aging; Apoptosis; Apoptosis Regulation Gene; Apoptotic; BAX gene; Bax protein; Biological; CDKN2A gene; Caspase; Cell Aging; Cell Cycle; Cell Death; Cell Membrane Permeability; Cells; Chronic; Clinical Treatment; Cytosol; DNA Damage; Data; Disease; Drug Targeting; Excision; Functional disorder; Genetic; Goals; In Vitro; Inflammatory; Intervention; Investigation; Kinetics; Knowledge; Lead; Link; Mediating; Mediator of activation protein; Microscopy; Minority; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Mus; Outer Mitochondrial Membrane; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Reporter; Resolution; Role; Stimulator of Interferon Genes; Stress; System; Tissues; Treatment Efficacy; Tumor Suppressor Proteins; Work; age related; base; cytochrome c; drug development; effectiveness testing; efficacy testing; experimental study; healthspan; healthy aging; improved; in vitro activity; in vivo; innovation; interest; live cell imaging; major outer membrane protein; mitochondrial dysfunction; mouse model; new therapeutic target; novel; novel therapeutics; preservation; pro-apoptotic protein; response; senescence; tissue degeneration; tool

PROJECT SUMMARY/ABSTRACT This application investigates the relationship between mitochondrial apoptotic stress, senescence and aging. Cellular senescence is a well-established driver of tissue and organismal aging, a process thought to be partly mediated via the induction of a chronic Senescence-associated secretory phenotype (SASP). Consequently, there is great interest in selectively targeting senescent cells as a strategy to promote healthy aging. Our work has demonstrated that mitochondrial dysfunction is a hallmark of cellular senescence and a driver of the SASP. Mitochondria are also major regulators of apoptosis, a process which involves mitochondrial outer membrane permeability (MOMP) and subsequent release of cytochrome c through the actions of the pro-apoptotic proteins BAX and BAK. We found that MOMP occurring in a small subset of mitochondria without inducing cell-death, a process known as minority MOMP (miMOMP) is a feature of cellular senescence and contributes to the SASP. We have also observed that miMOMP leads to the release of cytosolic mtDNA which can engage the cGAS/STING pathway, a major regulator of the SASP. These data led us to hypothesize that miMOMP is a major contributor to the senescent phenotype and may be a novel target for interventions aiming to counteract aging and age-related pathology. We will conduct in vitro experiments in which we will explore the molecular mechanisms of why miMOMP occurs during senescence and how it impacts on senescence and the SASP (aims 1 and 2). Finally, we will investigate the impact of genetic and pharmacologic interventions which alleviate miMOMP during aging in vivo (aim 3). For that, we will unravel the relative impact of conditional deletion of BAX/BAK (which drive miMOMP) and/or Apaf1 (essential for MOMP- dependent caspase activation) during aging in vivo. Finally, we will test the effectiveness of miMOMP-inhibiting drugs on improving key phenotypes in aging mice. Our ultimate goal is to identify new interventions that target senescent cells to alleviate age- related dysfunction.

项目摘要/摘要 这个应用程序研究了线粒体凋亡应激、 衰老和衰老。细胞衰老是组织和组织的公认驱动因素 生物体衰老，这一过程被认为部分是通过诱导慢性 衰老相关分泌表型(SASP)。因此，人们对……非常感兴趣 选择性地以衰老细胞为目标，作为促进健康衰老的一种策略。我们的工作已经完成 证明线粒体功能障碍是细胞衰老的标志和驱动因素 SASP。线粒体也是细胞凋亡的主要调节者，这一过程涉及 线粒体外膜通透性(MOMP)和随后细胞色素c的释放 通过促凋亡蛋白BAX和BAK的作用。我们发现MOMP的发生 在一小部分线粒体中，不会导致细胞死亡，这一过程被称为少数 MOMP(MiMOMP)是细胞衰老的一种特征，与SASP有关。我们有 还观察到miMOMP导致胞质mtDNA的释放，这可以与 CGAS/STING途径，是SASP的主要调节因子。这些数据使我们假设 MiMOMP是衰老表型的主要贡献者，可能是一种新的靶点 旨在对抗衰老和年龄相关病理的干预措施。 我们将进行体外实验，在其中我们将探索为什么 MiMOMP在衰老过程中发生及其对衰老和SASP的影响(AIMS 1 和2)。最后，我们将调查遗传和药物干预的影响 减轻体内老化过程中的miMOMP(目标3)。为此，我们将揭开 有条件地删除BAX/BAK(驱动miMOMP)和/或Apaf1(对MOMP至关重要- 依赖半胱氨酸天冬氨酸酶激活)。最后，我们将测试 MiMOMP抑制药改善衰老小鼠主要表型的研究。 我们的最终目标是确定针对衰老细胞的新干预措施，以延缓衰老- 相关功能障碍。