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Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence.

Abstract：

: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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Vizioli MG,Liu T,Miller KN,Robertson NA,Gilroy K,Lagnado AB,Perez-Garcia A,Kiourtis C,Dasgupta N,Lei X,Kruger PJ,Nixon C,Clark W,Jurk D,Bird TG,Passos JF,Berger SL,Dou Z,Adams PD

doi

10.1101/gad.331272.119

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

428-445

issue

5-6

eissn

0890-9369

issn

1549-5477

pii

gad.331272.119

journal_volume

34

pub_type

杂志文章

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