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

Maria Grazia Vizioli, Tianhui Liu, Karl N. Miller, Neil A. Robertson, Kathryn Gilroy, Anthony B. Lagnado, Arantxa Perez-Garcia, Christos Kiourtis, Nirmalya Dasgupta, Xue Lei, Patrick J. Kruger, Colin Nixon, William Clark, Diana Jurk, Thomas G. Bird, João F. Passos, Shelley L. Berger, Zhixun Dou, Peter D. Adams

Research output: Contribution to journalArticle

5 Scopus citations

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 nuclearencoded 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 drugbased interventions to inhibit the proaging SASP.

Original languageEnglish (US)
Pages (from-to)428-445
Number of pages18
JournalGenes and Development
Volume34
Issue number5
DOIs
StatePublished - Mar 1 2020

Keywords

  • Cytoplasmic chromatin
  • Inflammation
  • Mitochondria
  • Senescence

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    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., & Adams, P. D. (2020). Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes and Development, 34(5), 428-445. https://doi.org/10.1101/gad.331272.119