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

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, Dr Laura Greaves, Dr Glyn Nelson, Professor Derek Mann, Dr Gabriele Saretzki, Professor Thomas von Zglinicki, Dr Viktor Korolchuk, Dr Joao Passos

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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-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.


Publication metadata

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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