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Lookup NU author(s): Dr Clara Correia Melo, Francisco Marques, Rhys Anderson, Dr Graeme Hewitt, Dr Bernadette Carroll, Dr Satomi Miwa, Dr Jodie Birch, Alina Merz, Dr Michael Rushton, Dr Michelle Charles, Dr Diana Jurk, Dr Rafal Czapiewski, Professor Laura GreavesORCiD, Dr Glyn NelsonORCiD, Professor Derek Mann, Dr Gabriele Saretzki, Professor Thomas von Zglinicki, Professor Viktor KorolchukORCiD, Dr Joao Passos
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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-1 beta-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-1 beta 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.
Author(s): Correia-Melo C, Marques FDM, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SWG, Czapiewski R, Greaves L, Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D, Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, Passos JF
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Year: 2016
Volume: 35
Issue: 7
Pages: 724-742
Print publication date: 01/04/2016
Online publication date: 04/02/2016
Acceptance date: 12/01/2016
Date deposited: 25/05/2016
ISSN (print): 0261-4189
ISSN (electronic): 1460-2075
Publisher: Wiley-Blackwell Publishing Ltd.
URL: http://dx.doi.org/10.15252/embj.201592862
DOI: 10.15252/embj.201592862
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