Roles of mitochondrial dynamics and mtDNA in senescence

该提案的长期目标是提供一个基本的机械理解 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，清除受损细胞以保持组织完整性， 防止肿瘤发生。衰老细胞的积累，表达大量的 炎性细胞因子，称为衰老相关分泌表型（SASP），是一种 是导致机体衰老的重要因素。在过去的十年里，研究已经确定了 破坏核膜（核纤层）的完整性，随后释放核DNA（nDNA） 作为衰老和早衰的主要触发因素，即早衰症。另 另一方面，实验证据长期以来一直暗示线粒体参与衰老和老化。然而，在这方面， 线粒体在衰老中的确切作用仍然未知。我们发现，在 衰老时，线粒体DNA（mtDNA）含量显著升高， 进行精细的融合。衰老细胞的基因表达分析显示， ABAT和RRM2B的上调，这两个基因是mtDNA合成所必需的， 上维护这些基因在老年小鼠中也会升高。我们发现药理学上 线粒体DNA合成抑制SASP，但影响衰老相关的生长 逮捕了这些发现揭示了线粒体DNA在SASP中的独特信号传导作用， 衰老过程中的线粒体重塑本建议旨在界定 核和线粒体途径在SASP中的意义与衰老相关， 衰老并研究线粒体动力学在激活中的调节和作用 SASP。

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.