Journal
EMBO JOURNAL
Volume 35, Issue 7, Pages 724-742Publisher
WILEY
DOI: 10.15252/embj.201592862
Keywords
ageing; inflammation; mitochondria; mTOR; senescence
Categories
Funding
- FP7-MITIN [HEALTH-F4-2008-223450]
- Medical Research Council Centre for Obesity and Related Metabolic Diseases
- BBSRC [BB/I020748/1, BB/K019260/1, BB/H022384/1, BB/K017314/1]
- Royal Society University Fellowship
- Foundation for Science and Technology (FCT), Portugal studentship through the GABBA Program
- University of Porto
- Newcastle University
- Biotechnology and Biological Sciences Research Council [BB/K017314/1, BB/K019260/1, BB/K017233/1, BB/M023389/1, BB/H022384/1, BB/F010966/1, BB/I020748/1, BB/J007803/1] Funding Source: researchfish
- Medical Research Council [G0700718, G0400192, MC_UU_12012/5/B, MR/K001949/1, MR/L016354/1, MR/K006312/1, MC_UU_12012/2, MC_G0802535] Funding Source: researchfish
- BBSRC [BB/K017314/1, BB/J007803/1, BB/K017233/1, BB/K019260/1, BB/I020748/1, BB/H022384/1, BB/F010966/1, BB/M023389/1] Funding Source: UKRI
- MRC [G0700718, MR/K001949/1, MR/L016354/1, MC_UU_12012/2, G0400192, MC_G0802535, MR/K006312/1] Funding Source: UKRI
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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.
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