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

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...

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Veröffentlicht in:Genes & development Jg. 34; H. 5-6; S. 428
Hauptverfasser: Vizioli, Maria Grazia, Liu, Tianhui, Miller, Karl N, Robertson, Neil A, Gilroy, Kathryn, Lagnado, Anthony B, Perez-Garcia, Arantxa, Kiourtis, Christos, Dasgupta, Nirmalya, Lei, Xue, Kruger, Patrick J, Nixon, Colin, Clark, William, Jurk, Diana, Bird, Thomas G, Passos, João F, Berger, Shelley L, Dou, Zhixun, Adams, Peter D
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.03.2020
Schlagworte:
Animals
Cell Nucleus - pathology
Cell Nucleus - physiology
Cellular Senescence - physiology
Chromatin - pathology
Cytoplasm - pathology
Gene Expression Regulation, Developmental - drug effects
Histone Deacetylase Inhibitors - pharmacology
Humans
Inflammation - physiopathology
Male
MAP Kinase Signaling System - physiology
Mice
Mice, Inbred C57BL
Mitochondria - drug effects
Mitochondria - pathology
Mitochondria - physiology
Reactive Oxygen Species - metabolism
Signal Transduction
Tumor Suppressor p53-Binding Protein 1 - metabolism
senescence
cytoplasmic chromatin
inflammation
mitochondria
ISSN:1549-5477, 1549-5477
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1549-5477
1549-5477
DOI:10.1101/gad.331272.119