Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence
Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence
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DOI：
10.1101/gad.331272.119
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发表时间：
2020-03-01
影响因子：
10.5
通讯作者：
Adams, Peter D.
中科院分区：
文献类型：
--
作者：
Vizioli, Maria Grazia;Liu, Tianhui;Adams, Peter D.
细胞衰老是一种有效的肿瘤抑制机制，但也有助于衰老和衰老相关疾病。衰老的特征在于稳定的细胞周期停滞和复杂的促炎分泌组，称为衰老相关分泌表型（SASP）。我们最近发现，从衰老细胞的细胞核中挤出的细胞质染色质片段（CCF）通过激活先天免疫细胞溶质DNA传感cGAS-STING途径触发SASP。然而，引发CCF形成的上游信号事件仍然未知。在这里，我们表明，线粒体功能障碍，与核编码的线粒体氧化磷酸化基因的下调，触发ROS-JNK逆行信号通路，驱动CCF的形成，因此SASP。JNK与53 BP 1连接，53 BP 1是一种负调节DNA双链断裂（DSB）末端切除和CCF形成的核蛋白。重要的是，我们发现低剂量HDAC抑制剂恢复了大多数核编码的线粒体氧化磷酸化基因的表达，改善了线粒体功能，并抑制了衰老细胞中的CCF和SASP。在小鼠模型中，HDAC抑制剂还抑制由衰老诱导的辐射和/或对乙酰氨基酚诱导的线粒体功能障碍引起的氧化应激、CCF、炎症和组织损伤。总的来说，我们的研究结果概述了一个扩展的细胞核逆行信号通路，启动形成CCF在衰老过程中，是一个潜在的目标，以药物为基础的干预措施，以抑制proaging SASP。
Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS-STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown. Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS-JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction. Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP.