title: 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 aROS-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.
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK GABBA Program, Abel Salazar Biomedical Sciences Institute University of Porto, Porto, Portugal.
authors: Clara
authors: C
authors: Correia-Melo
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Francisco D M
authors: FD
authors: Marques
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Rhys
authors: R
authors: Anderson
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Graeme
authors: G
authors: Hewitt
authors: Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
authors: Rachael
authors: R
authors: Hewitt
authors: Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
authors: John
authors: J
authors: Cole
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Bernadette M
authors: BM
authors: Carroll
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Satomi
authors: S
authors: Miwa
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Jodie
authors: J
authors: Birch
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Alina
authors: A
authors: Merz
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Michael D
authors: MD
authors: Rushton
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Michelle
authors: M
authors: Charles
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Diana
authors: D
authors: Jurk
authors: Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
authors: Stephen W G
authors: SW
authors: Tait
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Rafal
authors: R
authors: Czapiewski
authors: Wellcome Trust Centre for Mitochondrial Research, Newcastle University Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
authors: Laura
authors: L
authors: Greaves
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Glyn
authors: G
authors: Nelson
authors: Transgenic RAD, Discovery Sciences, AstraZeneca, Mölndal, Sweden.
authors: Mohammad
authors: M
authors: Bohlooly-Y
authors: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors: Sergio
authors: S
authors: Rodriguez-Cuenca
authors: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors: Antonio
authors: A
authors: Vidal-Puig
authors: Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Derek
authors: D
authors: Mann
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Gabriele
authors: G
authors: Saretzki
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Giovanni
authors: G
authors: Quarato
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Douglas R
authors: DR
authors: Green
authors: Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
authors: Peter D
authors: PD
authors: Adams
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Thomas
authors: T
authors: von Zglinicki
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
authors: Viktor I
authors: VI
authors: Korolchuk
authors: Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK joao.passos@ncl.ac.uk.
authors: João F
authors: JF
authors: Passos
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D010641:Phenotype
keywords: ageing; inflammation; mTOR; mitochondria; senescence