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.

这一建议的长期目标是提供一个基本的机制的理解