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线粒体DNA复制压力会触发核体处置的亲炎性内体路径

Laura E Newman¹, Sammy Weiser Novak¹, Gladys R Rojas¹

¹Salk Institute for Biological Studies, La Jolla, CA, USA.

Nature cell biology

|February 9, 2024

概括

线粒体DNA (mtDNA) 的压力会导致扩大的核离子离开线粒体,通过cGAS-STING通路引发炎症. 这表明,针对受损mtDNA的质量控制途径可能是一个治疗目标.

科学领域:

细胞生物学细胞生物学
免疫学免疫学免疫学
遗传学是一个遗传学.

背景情况:

线粒体DNA (mtDNA) 作为损伤相关分子模式 (DAMP) 起作用,在线粒体释放时启动炎症.
由TFAM枯竭或病毒感染引起的mtDNA压力导致线粒体变化和cGAS-STING通路激活.
线粒体/核体动力学,mtDNA释放和免疫信号之间的联系尚未完全理解.

研究的目的:

阐明异常线粒体,核体动力学,mtDNA释放和cGAS-STING激活之间的关系.
确定mtDNA释放和随后的免疫反应背后的机制.
探索针对mtDNA介导炎症的潜力.

主要方法:

研究了mtDNA复制压力和简单疹病毒-1感染模型.
分析了线粒体和核细胞的形态和动态.
通过细胞区间追踪核体的贩运.
评估了cGAS-STING通路的激活.

主要成果:

与TFAM结合的扩大核质在复制压力或病毒感染下离开线粒体.
核体扩大是由于复制应激阻断线粒体裂变而产生的,从而创建了一个检查点.
慢性检查点的接触导致核体进入内体,导致破裂和cGAS-STING激活.
复制无能力的核子体通过线粒体-内体质量控制途径被消除.

结论:

一个线粒体-内体质量控制途径消除了复制无能核子.
这种途径通过mtDNA释放的激活可以导致致病性炎症.
针对这种途径可能为mtDNA介导的炎症性疾病和病毒感染提供治疗策略.

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