Mitonuclear signaling pathways in senescence-associated inflammation

衰老相关炎症中的线粒体核信号通路

• 批准号: 10525640
• 负责人: Karl Nathan Miller
• 金额: $ 11.8万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525640
• 关键词: Ablation; Acute; Advisory Committees; Age; Aging; Bioinformatics; Cell Aging; Cell Nucleus; Cell physiology; Cells; Cellular Structures; Chromatin; Chronic; Chronic Disease; Cytoplasm; DNA; DNA Damage; DNA Repair Gene; Disease; Environment; Epigenetic Process; Excision; Gene Expression; Gene Expression Profiling; Goals; Growth; Homeostasis; Human; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Iron; Link; Longevity; MAPK8 gene; Malignant neoplasm of liver; Mammalian Cell; Measures; Mediating; Membrane Potentials; Mentors; Metabolism; Metals; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mus; Organism; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Pharmacology; Pharmacotherapy; Phase; Phenotype; Phosphorylation; Prevention; Primary carcinoma of the liver cells; Process; Production; Proteins; Publishing; Regulation; Research; Role; Scientist; Signal Pathway; Signal Transduction; Site; Source; Stimulator of Interferon Genes; Stress; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Tumor Suppressor Proteins; aged; antagonist; biological adaptation to stress; cell age; chronic liver inflammation; cytokine; design; experimental study; healthspan; healthy aging; human disease; immune clearance; improved; in vivo; inhibitor; innovation; interest; mitochondrial dysfunction; new therapeutic target; novel; nuclease; p53-binding protein 1; response; senescence; side effect; single-cell RNA sequencing; success; therapeutic target; tool; transcription factor

PROJECT SUMMARY Cellular senescence is a hallmark of the aging process and contributes to chronic disease vulnerability. Although senescence acts acutely as a tumor suppressor mechanism, chronically it also contributes to inflammation in aged tissue through the senescence-associated secretory phenotype (SASP). Hence, removal of senescent cells in vivo improves healthspan and lifespan, and rescues pathology associated with a plethora of phenotypes and diseases of aging. However, pharmacological “senolytic” approaches tend to have toxic side effects, likely limiting the utility of senolytics as tools to promote healthy aging. As proof-of-concept for an alternative approach, suppression of SASP in vivo reduces chronic liver inflammation and delays onset of hepatocellular carcinoma. Recently, we have shown that SASP is dependent on expulsion of cytosolic chromatin fragments (CCF) from the nucleus into the cytoplasm of senescent cells. Senescent cells harbor dysfunctional mitochondria, as reflected by decreased membrane potential, elevated ROS production, decreased mitophagic turnover, and altered intermediary metabolism. We have recently linked dysfunctional mitochondria in senescent cells to CCF production, and hence SASP, through a retrograde mitonuclear signaling pathway. This pathway involves mitochondrial ROS-mediated activation of the kinase JNK1/2, which is required for CCF formation, and the DNA repair protein 53BP1, which suppresses CCF formation. However, the mechanism linking JNK1/2 to 53BP1 is unknown. Extending these findings, studies in non-vertebrate organisms also suggest that mitochondria-nucleus retrograde signaling pathways can modify aging and longevity, altogether suggesting that identification and targeting of these pathways has therapeutic potential in the treatment of age-associated diseases. However, these pathways are poorly understood in mammalian systems. I hypothesize that mitonuclear signaling in senescent cells modulates the senescent cell phenotype and hence senescence-associated human disease. This proposal has two Aims in the mentored K99 phase, to: 1) Determine the mechanism by which JNK1/2 regulates 53BP1 to induce CCF formation; 2) Investigate the 53BP1-independent role of JNK1/2 senescent cells; and an additional Aim in the independent R00 phase, to 3) Investigate the role of mitochondria-mediated suppression of ATF4 and crosstalk between other stress responses in senescent cells. Elucidation of these mitonuclear signaling pathways in mammalian cells is of broad general interest to all biologists but can also identify therapeutic targets for reduction of SASP. This approach can uncover alternatives to senolytic drugs for treatment of age-associated disease and promote healthy aging.

项目总结 细胞衰老是衰老过程的一个标志，也是慢性病脆弱性的原因之一。 尽管衰老在很大程度上是一种肿瘤抑制机制，但从长期来看，它也有助于 衰老相关分泌表型(SASP)在老年组织中的炎症。因此，删除 体内的衰老细胞可以改善健康和寿命，并挽救与过多相关的病理 衰老的表型和疾病。然而，药理上的“解感”方法往往是有毒的。 副作用，可能限制了感觉剂作为促进健康衰老的工具的用途。作为概念验证 另一种方法是，在体内抑制SASP可减少慢性肝脏炎症并延迟发病 肝细胞癌。 最近，我们已经证明，SASP依赖于胞浆染色质片段(CCF)从 细胞核进入衰老细胞的细胞质。衰老的细胞含有功能失调的线粒体，如 反映为膜电位下降，ROS产生增加，丝裂原周转减少，以及 改变了中间代谢。我们最近将衰老细胞中功能失调的线粒体与 CCF的产生，因此SASP，通过逆行有丝分裂核信号通路。这条路 涉及线粒体ROS介导的激酶JNK1/2的激活，这是形成CCF所必需的， 以及DNA修复蛋白53BP1，它抑制CCF的形成。然而，机制链接 JNK1/2至53BP1未知。 扩展这些发现，对非脊椎动物的研究还表明，线粒体-核 逆行信号通路可以改变衰老和寿命，总之，这表明识别和 靶向这些通路在治疗年龄相关疾病方面具有治疗潜力。然而， 在哺乳动物系统中，人们对这些途径知之甚少。 我假设衰老细胞中的有丝分裂信号调节衰老细胞的表型，因此 与衰老相关的人类疾病。此建议书在指导K99阶段有两个目标：1) 确定JNK1/2调控53BP1诱导CCF形成的机制；2)研究 JNK1/2衰老细胞的53BP1非依赖性作用；以及独立R00的另一个目的 阶段，以3)研究线粒体介导的ATF4抑制和相互间串扰的作用 衰老细胞中的其他应激反应。这些有丝分裂核信号转导途径的阐明 哺乳动物细胞对所有生物学家都有广泛的兴趣，但也可以确定治疗的靶点 减少SASP。这种方法可以发现治疗与年龄相关的变态反应药物的替代药物。 预防疾病，促进健康衰老。