Mitochondria are required for pro-ageing features of the senescent phenotype

Clara Correia-Melo, Francisco D.M. Marques, Rhys Anderson, Graeme Hewitt, Rachael Hewitt, John Cole, Bernadette M. Carroll, Satomi Miwa, Jodie Birch, Alina Merz, Michael D. Rushton, Michelle Charles, Diana Jurk, Stephen W.G. Tait, Rafal Czapiewski, Laura Greaves, Glyn Nelson, Mohammad Bohlooly-Y, Sergio Rodriguez-Cuenca, Antonio Vidal-PuigDerek Mann, Gabriele Saretzki, Giovanni Quarato, Douglas R. Green, Peter D. Adams, Thomas Von Zglinicki, Viktor I. Korolchuk, João F. Passos

Research output: Contribution to journalArticle

211 Scopus citations

Abstract

Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro-inflammatory and pro-oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent-associated changes are dependent on mitochondria, particularly the pro-inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC-1β-dependent mitochondrial biogenesis, contributing to a ROS-mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC-1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.

Original languageEnglish (US)
Pages (from-to)724-742
Number of pages19
JournalEMBO Journal
Volume35
Issue number7
DOIs
StatePublished - Apr 1 2016

Keywords

  • ageing
  • inflammation
  • mTOR
  • mitochondria
  • senescence

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Correia-Melo, C., Marques, F. D. M., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B. M., Miwa, S., Birch, J., Merz, A., Rushton, M. D., Charles, M., Jurk, D., Tait, S. W. G., Czapiewski, R., Greaves, L., Nelson, G., Bohlooly-Y, M., Rodriguez-Cuenca, S., ... Passos, J. F. (2016). Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO Journal, 35(7), 724-742. https://doi.org/10.15252/embj.201592862