Mitochondria are required for pro-ageing features of the senescent phenotype.
Mitochondria are required for pro-ageing features of the senescent phenotype.
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DOI：
10.15252/embj.201592862
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Passos JF
中科院分区：
文献类型：
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作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
细胞衰老是肿瘤抑制的重要机制和衰老的驱动因素。这两种功能都依赖于衰老表型的发展，衰老表型涉及促炎和促氧化信号的过度产生。然而，调节这些表型的确切机制仍然知之甚少。在这里，我们展示了线粒体在细胞衰老中的关键作用。在多种衰老模型中，线粒体的缺失减少了衰老效应物和表型的谱，同时通过增强糖酵解保持ATP的产生。通过RNA测序进行的全球转录组学分析显示，大量衰老相关的变化依赖于线粒体，特别是促炎表型。从机制上讲，我们发现ATM、Akt和mTORC1磷酸化级联将DNA损伤反应（DDR）信号整合到PGC - 1β依赖性线粒体生物发生中，有助于ROS介导的DDR激活和细胞周期阻滞。最后，我们证明，通过mTORC1抑制或PGC‐1β缺失，体内线粒体含量的减少可以防止衰老小鼠肝脏的衰老。我们的研究结果表明，线粒体是干预的候选目标，以减少老化组织中衰老的有害影响。
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.