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

Correia-Melo, C. et al. (2016) Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO Journal, 35, pp. 724-742. (doi:10.15252/embj.201592862) (PMID:26848154) (PMCID:PMC4818766)

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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‐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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cole, Mr John and Marques, Dr Francisco and Adams, Professor Peter and Hewitt, Miss Rachael and Tait, Professor Stephen
Authors: 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., Vidal-Puig, A., Mann, D., Saretzki, G., Quarato, G., Green, D. R., Adams, P. D., von Zglinicki, T., Korolchuk, V. I., and Passos, J. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in EMBO Journal 35:724-742
Publisher Policy:Reproduced under a Creative Commons License

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