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.
Highlights
Cell senescence is an important tumour suppressor mechanism and driver of ageing
By conducting a cytokine array, we found that the secretion of major senescence-associated secretory phenotype (SASP) factors such as IL-6, IL-8, GRO and MCP-1 was drastically reduced following mitochondrial clearance (Fig 1H)
Chemical and genetic interventions impacting on the mitochondrial electron transport chain have been shown to enhance oncogene-induced senescence (OIS) (Moiseeva et al, 2009); to date, no study has effectively evaluated the necessity of mitochondria for the induction of the senescent phenotype
Summary
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. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent-associated changes are dependent on mitochondria, the pro-inflammatory phenotype. We show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC-1b-dependent mitochondrial biogenesis, contributing to a ROS-mediated activation of the DDR and cell cycle arrest. We demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC-1b 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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