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 该应用调查了线粒体凋亡应激之间的关系， 衰老和衰老。细胞衰老是组织和 有机老化，这一过程被认为是通过慢性诱导而部分介导的 衰老相关的分泌表型（SASP）。因此，对 有选择地将衰老细胞作为促进健康衰老的策略。我们的工作有 证明线粒体功能障碍是细胞衰老的标志，也是 SASP。线粒体也是凋亡的主要调节剂，这一过程涉及 线粒体外膜通透性（MOMP）和随后释放细胞色素c 通过促凋亡蛋白Bax和Bak的作用。我们发现MOMP发生了 在一小部分线粒体的一小部分中，没有诱导细胞死亡，这一过程称为少数 MOMP（MIMOMP）是细胞衰老的特征，并有助于SASP。我们有 还观察到，MIMOMP导致胞质mtDNA的释放，这可以参与 CGAS/STING PATHWAY，SASP的主要调节器。这些数据导致我们假设 Mimomp是衰老表型的主要贡献者，可能是 旨在抵消衰老和与年龄有关的病理学的干预措施。 我们将进行体外实验，其中我们将探讨为什么 模仿发生在衰老期间及其对衰老和SASP的影响（目标1） 和2）。最后，我们将研究遗传和药理干预措施的影响 减轻体内衰老期间的MIMOMP（AIM 3）。为此，我们将揭示 Bax/Bak（驱动Mimomp）和/或APAF1的有条件删除（对于MOMP-必不可少的 在体内衰老期间，依赖性caspase激活）。最后，我们将测试 模拟抑制药物可以改善衰老小鼠的关键表型。 我们的最终目标是确定针对衰老细胞以减轻年龄的新干预措施 - 相关功能障碍。