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Mitochondria are required for pro‐ageing features of the senescent phenotype
Author(s) -
CorreiaMelo Clara,
Marques Francisco DM,
Anderson Rhys,
Hewitt Graeme,
Hewitt Rachael,
Cole John,
Carroll Bernadette M,
Miwa Satomi,
Birch Jodie,
Merz Alina,
Rushton Michael D,
Charles Michelle,
Jurk Diana,
Tait Stephen WG,
Czapiewski Rafal,
Greaves Laura,
Nelson Glyn,
BohloolyY Mohammad,
RodriguezCuenca Sergio,
VidalPuig Antonio,
Mann Derek,
Saretzki Gabriele,
Quarato Giovanni,
Green Douglas R,
Adams Peter D,
Zglinicki Thomas,
Korolchuk Viktor I,
Passos João F
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201592862
Subject(s) - biology , senescence , mitochondrion , microbiology and biotechnology , phenotype , ageing , effector , mitochondrial biogenesis , transcriptome , dna damage , genetics , gene expression , gene , dna
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 mTORC 1 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 mTORC 1 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.