Mitochondria are required for pro‐ageing features of the senescent phenotype

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.

Tau protein aggregation is associated with cellular senescence in the brain

“…Mitochondrial dysfunction is obligatory for SASP production and cellular senescence (Correia‐Melo et al, 2016; Hutter et al, 2004). To examine mitochondrial bioenergetics, we performed high‐resolution respirometry to yield accurate quantitative measurements of oxidative phosphorylation in response to specific substrates for complex I, complex II, fat oxidation, and electron‐transfer system (ETS) capacity.…”

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

“…The mitochondrial mass increased following Tyr stimulation, as shown by the mitochondrial DNA copy number using mitoCytb and mitoNd1 (Figure 3a). Since previous studies have shown that increased mitochondrial biogenesis was part of the senescent phenotype, we measured the expression levels of its main transcriptional co‐activators, PGC‐1α and PGC‐1β (Correia‐Melo et al, 2016). mRNA analysis showed that PGC‐1β expression was increased with Tyr, while PGC‐1α was unchanged (Figure 3b).…”

“…Thus, mitochondrial dysfunction through ROS accumulation likely contributes to DDR establishment and senescence. In a previous study, Correia‐Melo et al (2016) reported that mitochondria were necessary for replicative and irradiation‐induced premature senescence in fibroblasts. In this case, they also observed mitochondrial ROS accumulation and increased mitochondrial mass, but the main drivers of senescence were mitochondrial biogenesis and PGC‐1β activation.…”

“…At the cellular level, converging evidence indicates that mitochondrial dysfunction and cellular senescence are interlinked processes (Ziegler, Wiley, & Velarde, 2015). This is well‐illustrated by the finding that complete removal of mitochondria from senescent cells prevents several features of cellular senescence (Correia‐Melo et al, 2016). Furthermore, during senescence, the mTOR/p70S6K kinase pathway has been shown to induce mitochondrial dysfunction and enhance ROS production, which stabilizes the DDR in a positive feedback loop (Correia‐Melo et al, 2016; Nacarelli, Azar, & Sell, 2015).…”

“…This is well‐illustrated by the finding that complete removal of mitochondria from senescent cells prevents several features of cellular senescence (Correia‐Melo et al, 2016). Furthermore, during senescence, the mTOR/p70S6K kinase pathway has been shown to induce mitochondrial dysfunction and enhance ROS production, which stabilizes the DDR in a positive feedback loop (Correia‐Melo et al, 2016; Nacarelli, Azar, & Sell, 2015). Currently, it remains unclear why damaged mitochondria accumulate in senescent cells, although it may involve increased biogenesis and/or disruption of mitophagy, a process which allows their elimination by the autophagy‐lysosome pathway (Korolchuk, Miwa, Carroll, & von Zglinicki, 2017).…”