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: 10664050
• 负责人: Joao Passos
• 金额: $ 42.33万
• 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/10664050
• 关键词: Aging; Apoptosis; Apoptosis Regulation Gene; Apoptotic; BAX gene; Bax protein; Biological; CDKN2A gene; Caspase; Cell Aging; Cell Cycle Arrest; Cell Death Induction; 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; Link; Mediating; Mediator; Minority; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Mus; Outer Mitochondrial Membrane; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Process; Reporter; Role; Stimulator of Interferon Genes; Stress; System; Tissues; Treatment Efficacy; Tumor Suppressor Proteins; Visualization; Work; age related; cytochrome c; drug development; effectiveness testing; efficacy testing; experimental study; healthspan; healthy aging; improved; in vitro activity; in vivo; innovation; interest; live cell imaging; mitochondrial dysfunction; mouse model; new therapeutic target; novel; novel therapeutics; pharmacologic; preservation; pro-apoptotic protein; response; senescence; superresolution microscopy; 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.

项目总结/摘要 本申请研究了线粒体凋亡应激， 衰老和老化。细胞衰老是组织和细胞衰老的公认驱动因素。 有机体衰老，这一过程被认为部分是通过诱导慢性衰老来介导的。 衰老相关分泌表型（SASP）。因此，人们对 选择性靶向衰老细胞作为促进健康衰老的策略。我们的工作 证明线粒体功能障碍是细胞衰老的标志，也是细胞衰老的驱动因素。 SASP。线粒体也是细胞凋亡的主要调节因子， 线粒体外膜通透性（MOMP）和随后的细胞色素c释放 通过促凋亡蛋白BAX和巴克的作用。我们发现MOMP发生在 在线粒体的一个小的子集，而不诱导细胞死亡，一个过程称为少数 MOMP（miMOMP）是细胞衰老的特征，并有助于SASP。我们有 还观察到miMOMP导致细胞质mtDNA的释放， cGAS/STING途径是SASP的主要调节因子。这些数据让我们假设， miMOMP是衰老表型的主要贡献者，并且可能是治疗衰老的新靶点。 旨在对抗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，在实验中我们将探索为什么 miMOMP发生在衰老过程中，以及它如何影响衰老和SASP（目标1 和2）。最后，我们将研究遗传和药物干预的影响， 减轻体内老化过程中的miMOMP（目的3）。为此，我们将揭示 条件性缺失BAX/巴克（其驱动miMOMP）和/或Apaf 1（对于MOMP-1是必需的）。 依赖的半胱天冬酶活化）。最后，我们将测试 miMOMP抑制药物改善衰老小鼠的关键表型。 我们的最终目标是确定新的干预措施，针对衰老细胞，以减轻年龄- 相关功能障碍。

项目成果

New Horizons in cellular senescence for clinicians.

• DOI: 10.1093/ageing/afad127
• 发表时间: 2023-07-01
• 期刊: AGE AND AGEING
• 影响因子: 6.7
• 作者: Witham, Miles D.;Granic, Antoneta;Miwa, Satomi;Passos, Joao F.;Richardson, Gavin D.;Sayer, Avan A.
• 通讯作者: Sayer, Avan A.

Determining the feasibility of characterising cellular senescence in human skeletal muscle and exploring associations with muscle morphology and physical function at different ages: findings from the MASS_Lifecourse Study.

• DOI: 10.1007/s11357-023-00869-4
• 发表时间: 2024-02
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Habiballa, Leena;Hruby, Adam;Granic, Antoneta;Dodds, Richard M.;Hillman, Susan J.;Jurk, Diana;Passos, Joao F.;Sayer, Avan A.
• 通讯作者: Sayer, Avan A.

Therapeutic Potential of Senolytics in Cardiovascular Disease.

• DOI: 10.1007/s10557-020-07075-w
• 发表时间: 2022-03
• 期刊: Cardiovascular drugs and therapy
• 影响因子: 3.4
• 作者: Dookun E;Passos JF;Arthur HM;Richardson GD
• 通讯作者: Richardson GD

Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.

• DOI: 10.1038/s41418-021-00917-6
• 发表时间: 2022-06
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Fernandez-Duran, Irene;Quintanilla, Andrea;Tarrats, Nuria;Birch, Jodie;Hari, Priya;Millar, Fraser R.;Lagnado, Anthony B.;Smer-Barreto, Vanessa;Muir, Morwenna;Brunton, Valerie G.;Passos, Joao F.;Acosta, Juan Carlos
• 通讯作者: Acosta, Juan Carlos

Bone Marrow Adiposity in Models of Radiation- and Aging-Related Bone Loss Is Dependent on Cellular Senescence.

• DOI: 10.1002/jbmr.4537
• 发表时间: 2022-05
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Chandra, Abhishek;Lagnado, Anthony B.;Farr, Joshua N.;Schleusner, Megan;Monroe, David G.;Saul, Dominik;Passos, Joao F.;Khosla, Sundeep;Pignolo, Robert J.
• 通讯作者: Pignolo, Robert J.