Roles of mitochondrial dynamics and mtDNA in senescence

线粒体动力学和 mtDNA 在衰老中的作用

• 批准号: 10344369
• 负责人: XIAO-FAN WANG
• 金额: $ 39.08万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10344369
• 关键词: Adopted; Affect; Aging; Cell Aging; Cell Nucleus; Cells; Cytosol; DNA; DNA Damage; DNA Maintenance; DNA Sequence Alteration; DNA biosynthesis; Defense Mechanisms; Degenerative Disorder; Extravasation; Gene Expression Profiling; Genes; Growth; Inflammatory; Lamin B1; Lamin Type A; Left; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Morphology; Mus; NF-kappa B; Nuclear; Nuclear Envelope; Nuclear Lamin; Nuclear Lamina; Nucleotides; Pathway interactions; Pharmacology; Phenotype; Physiological; Ploidies; Premature aging syndrome; Process; Production; Progeria; Regulation; Role; Signal Transduction; Source; Stimulator of Interferon Genes; Stress; TLR9 gene; Testing; Tissues; Up-Regulation; Viral; Zalcitabine; ataxia telangiectasia mutated protein; cell injury; chemokine; cytokine; human old age (65+); novel; prevent; programs; response; senescence; tumorigenesis

This proposal's long-term objective is to provide a fundamental mechanistic understanding of the role of nucleus vs. mitochondria in the activation of the senescence program. Senescence is a central cellular defense mechanism that removes damaged cells to maintain tissue integrity and prevent tumorigenesis. The accumulation of senescent cells, which express a copious amount of inflammatory cytokines, termed senescence-associated secretory phenotype (SASP), is a significant contributing factor to organismal aging. In the last decade, studies have identified the disruption of nuclear membrane (lamina) integrity and subsequent release of nuclear DNA (nDNA) to the cytosol as the primary trigger of senescence and premature aging, progeria. On the other hand, experimental evidence has long implied mitochondria in senescence and aging. However, the exact role of mitochondria in senescence remains unknown. We have found that during senescence, mitochondrial DNA (mtDNA) contents were elevated significantly and mitochondria undergo elaborate fusion. Gene expression analysis of senescent cells revealed coordinated upregulation of ABAT and RRM2B, two genes that are required for mtDNA synthesis and maintenance. These genes are also elevated in mice of old age. We found that pharmacological inhibition of mtDNA synthesis suppressed SASP but did affect senescence-associated growth arrest. These findings uncover a unique signaling role of mtDNA in SASP and coordinated mitochondrial remodeling during senescence. This proposal aims to delineate the functional significance of the nuclear and mitochondrial pathway in SASP associated with senescence and aging and investigate the regulation and roles of mitochondrial dynamics in the activation of SASP.

该提案的长期目标是提供对 细胞核与线粒体在衰老程序激活中的作用。衰老是一种 中央细胞防御机制，清除受损细胞以维持组织完整性和 预防肿瘤发生。衰老细胞的积累，表达大量 炎症细胞因子，称为衰老相关分泌表型（SASP），是一种 机体衰老的重要影响因素。在过去十年中，研究发现 破坏核膜（核纤层）完整性并随后释放核 DNA (nDNA) 细胞质是衰老和过早衰老、早衰的主要触发因素。另一方面 另一方面，实验证据长期以来表明线粒体与衰老和老化有关。然而， 线粒体在衰老中的确切作用仍不清楚。我们发现，期间 衰老过程中，线粒体DNA（mtDNA）含量显着升高，线粒体 进行精心的融合。衰老细胞的基因表达分析揭示了协调 ABAT 和 RRM2B 的上调，这是 mtDNA 合成所需的两个基因， 维护。这些基因在老年小鼠中也升高。我们发现药理 抑制 mtDNA 合成会抑制 SASP，但确实会影响衰老相关的生长 逮捕。这些发现揭示了 mtDNA 在 SASP 和协调中的独特信号作用 衰老过程中的线粒体重塑。该提案旨在界定功能 核和线粒体途径在 SASP 中与衰老相关的重要性 衰老并研究线粒体动力学在激活中的调节和作用 SASP。