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

Vizioli, M. G. et al. (2020) Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes and Development, 34(5-6), pp. 428-445. (doi: 10.1101/gad.331272.119) (PMID:32001510) (PMCID:PMC7050483)

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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.

Item Type:Articles
Keywords:Cytoplasmic chromatin, inflammation, mitochondria, senescence.
Glasgow Author(s) Enlighten ID:Vizioli, Dr Maria Grazia and Bird, Dr Thomas and Nixon, Mr Colin and Perez, Ms Arantxa and Clark, Mr William and Robertson, Mr Neil and Adams, Professor Peter and Gilroy, Dr Kathryn and Kiourtis, Christos
Authors: Vizioli, M. G., Liu, T., Miller, K. N., Robertson, N. A., Gilroy, K., Lagnado, A. B., Perez-Garcia, A., Kiourtis, C., Dasgupta, N., Lei, X., Kruger, P. J., Nixon, C., Clark, W., Jurk, D., Bird, T. G., Passos, J. F., Berger, S. L., Dou, Z., and Adams, P. D.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Genes and Development
Publisher:Cold Spring Harbor Laboratory Press
ISSN (Online):1549-5477
Published Online:30 January 2020
Copyright Holders:Copyright © 2020 Vizioli et al.
First Published:First published in Genes and Development 34(5-6): 428-445
Publisher Policy:Reproduced under a Creative Commons License

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