Roles of mitochondrial dynamics and mtDNA in senescence

这项提议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，移除受损细胞，以保持组织完整性和 预防肿瘤的发生。衰老细胞的积累，它表达大量的 炎性细胞因子，称为衰老相关分泌表型(SASP)，是一种 是导致生物老化的重要因素。在过去的十年里，研究发现了 核膜(膜)完整性的破坏和随后核DNA(NDNA)的释放 把胞浆作为衰老和早衰、早衰的主要触发物。另一方面 另一方面，实验证据长期以来一直暗示线粒体与衰老和衰老有关。然而， 线粒体在衰老中的确切作用仍不清楚。我们发现在这个过程中 衰老后线粒体DNA(MtDNA)含量显著升高，线粒体 经历了精心的融合。衰老细胞基因表达分析显示协调 上调线粒体DNA合成所需的两个基因abat和RRM2B，以及 维修。这些基因在老年小鼠中也会升高。我们发现从药理上讲 抑制线粒体DNA合成抑制SASP，但确实影响衰老相关的生长 逮捕。这些发现揭示了线粒体DNA在SASP中的独特信号作用 衰老过程中线粒体的重塑。这项建议旨在划定功能界别 SASP中核和线粒体途径与衰老和衰老的关系 并探讨线粒体动力学在线粒体活化中的调节和作用 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.