TY - JOUR
T1 - Mitochondria are required for pro-ageing features of the senescent phenotype
AU - Correia-Melo, Clara
AU - Marques, Francisco D.M.
AU - Anderson, Rhys
AU - Hewitt, Graeme
AU - Hewitt, Rachael
AU - Cole, John
AU - Carroll, Bernadette M.
AU - Miwa, Satomi
AU - Birch, Jodie
AU - Merz, Alina
AU - Rushton, Michael D.
AU - Charles, Michelle
AU - Jurk, Diana
AU - Tait, Stephen W.G.
AU - Czapiewski, Rafal
AU - Greaves, Laura
AU - Nelson, Glyn
AU - Bohlooly-Y, Mohammad
AU - Rodriguez-Cuenca, Sergio
AU - Vidal-Puig, Antonio
AU - Mann, Derek
AU - Saretzki, Gabriele
AU - Quarato, Giovanni
AU - Green, Douglas R.
AU - Adams, Peter D.
AU - Von Zglinicki, Thomas
AU - Korolchuk, Viktor I.
AU - Passos, João F.
N1 - Funding Information:
AV-P was funded by FP7-MITIN (HEALTH-F4-2008-223450) and Medical Research Council Centre for Obesity and Related Metabolic Diseases; SM is funded by a BBSRC grant BB/I020748/1, GN by a BBSRC grant BB/K019260/1 and VIK by BBSRC; SWGT is supported by a Royal Society University Fellowship, GH is supported by a case studentship from BBSRC, CCM is supported by Foundation for Science and Technology (FCT), Portugal studentship through the GABBA Program, University of Porto and Newcastle University, and JFP is supported by a David Phillips Fellowship provided by BBSRC BB/H022384/1 and a BBSRC grant BB/K017314/1.
Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
KW - ageing
KW - inflammation
KW - mitochondria
KW - mTOR
KW - senescence
UR - http://www.scopus.com/inward/record.url?scp=84959065037&partnerID=8YFLogxK
U2 - 10.15252/embj.201592862
DO - 10.15252/embj.201592862
M3 - Article
C2 - 26848154
AN - SCOPUS:84959065037
SN - 0261-4189
VL - 35
SP - 724
EP - 742
JO - EMBO Journal
JF - EMBO Journal
IS - 7
ER -