Roles of mitochondrial dynamics and mtDNA in senescence

摘要 这个建议的长期目标是提供一个基本的机械理解的作用的核心 vs.线粒体在衰老过程中的作用。衰老是一种中枢细胞防御 清除受损细胞以保持组织完整性和防止肿瘤发生的机制。的 衰老细胞的积累，表达大量的炎性细胞因子， 衰老相关分泌表型（SASP）是生物体衰老的重要因素。在 在过去的十年中，研究已经确定了核膜（纤层）完整性的破坏和随后的 核DNA（nDNA）释放到胞质溶胶作为衰老和过早衰老的主要触发因素， 早老症另一方面，实验证据早就暗示线粒体在衰老和老化中。 然而，线粒体在衰老中的确切作用仍然未知。我们发现，在 衰老过程中，线粒体DNA含量显著升高，线粒体经历了 精细的融合衰老细胞的基因表达分析揭示了ABAT的协同上调， RRM2B是线粒体DNA合成和维持所需的两个基因。这些基因也在 老年老鼠我们发现，药物抑制线粒体DNA合成抑制SASP，但不影响 衰老相关的生长停滞。这些发现揭示了线粒体DNA在SASP中的独特信号作用， 在衰老过程中协调线粒体重塑。本建议旨在界定 核和线粒体途径在SASP中的意义与衰老和老化相关， 探讨线粒体动力学在SASP激活中的调控和作用。

Abstract 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.