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

• Clara Correia‐Melo ^[5] ; Francisco DM Marques ^[4] ; Rhys Anderson ^[4] ; Graeme Hewitt ^[4] ; Rachael Hewitt ^[2] ; John Cole ^[2] ; Bernadette M Carroll ^[4] ; Satomi Miwa ^[4] ; Jodie Birch ^[4] ; Alina Merz ^[4] ; Michael D Rushton ^[4] ; Michelle Charles ^[4] ; Diana Jurk ^[4] ; Stephen WG Tait ^[2] ; Rafal Czapiewski ^[4] ; Laura Greaves ^[6] ; Glyn Nelson ^[4] ; Mohammad Bohlooly‐Y ^[7] ; Sergio Rodriguez‐Cuenca ^[8] ; Antonio Vidal‐Puig ^[8] ; Derek Mann ^[3] ; Gabriele Saretzki ^[4] ; Giovanni Quarato ^[1] ; Douglas R Green ^[1] ; Peter D Adams ^[2] ; Thomas von Zglinicki ^[4] ; Viktor I Korolchuk ^[4] ; João F Passos ^[4]
  1. [1] St. Jude Children's Research Hospital

     St. Jude Children's Research Hospital

     Estados Unidos

     
  2. [2] University of Glasgow

     University of Glasgow

     Reino Unido

     
  3. [3] Newcastle University

     Newcastle University

     Reino Unido

     
  4. [4] 1 Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality Newcastle University Institute for Ageing Newcastle University Newcastle upon Tyne UK
  5. [5] 1 Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality Newcastle University Institute for Ageing Newcastle University Newcastle upon Tyne UK; 2 GABBA Program Abel Salazar Biomedical Sciences Institute University of Porto Porto Portugal
  6. [6] 4 Wellcome Trust Centre for Mitochondrial Research Newcastle University Centre for Brain Ageing and Vitality Newcastle University Newcastle upon Tyne UK
  7. [7] 5 Transgenic RAD, Discovery Sciences AstraZeneca Mölndal Sweden
  8. [8] 6 Metabolic Research Laboratories Wellcome Trust‐MRC Institute of Metabolic Science Addenbrooke's Hospital University of Cambridge Cambridge UK

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 35, Nº. 7, 2016, págs. 724-742
• Idioma: inglés
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• Resumen

  • 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.