| First Author | Correia-Melo C | Year | 2016 |
| Journal | EMBO J | Volume | 35 |
| Issue | 7 | Pages | 724-42 |
| PubMed ID | 26848154 | Mgi Jnum | J:231536 |
| Mgi Id | MGI:5771726 | Doi | 10.15252/embj.201592862 |
| Citation | Correia-Melo C, et al. (2016) Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 35(7):724-42 |
| abstractText | 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 preservingATPproduction via enhanced glycolysis. Global transcriptomic analysis byRNAsequencing revealed that a vast number of senescent-associated changes are dependent on mitochondria, particularly the pro-inflammatory phenotype. Mechanistically, we show that theATM, Akt andmTORC1 phosphorylation cascade integrates signals from theDNAdamage response (DDR) towardsPGC-1beta-dependent mitochondrial biogenesis, contributing to aROS-mediated activation of theDDRand cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial contentin vivo, by eithermTORC1 inhibition orPGC-1beta 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. |
