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dc.contributor.authorCorreia-Melo, Clara-
dc.descriptionPhD Thesisen_US
dc.description.abstractCellular senescence, the irreversible loss of proliferating capacity of somatic cells, is an important tumour suppressor mechanism but also driver of ageing. These somehow contradictory functions are dependent on the development of the so-called senescent phenotype, which involves over-production of pro-inflammatory and pro-oxidant signals, however the exact mechanisms underlying its induction remain incompletely understood. In this thesis we aimed to understand how mitochondria and pro-inflammatory factors interact during senescence and how they contribute to the senescent phenotype. Firstly, we show that mitochondria are critical for the establishment and maintenance of cell senescence. Elimination of mitochondria rejuvenated senescent human fibroblasts, abrogating the pro-inflammatory phenotype, heterochromatin foci and expression of cyclin-dependent kinase inhibitors p21 and p16. Importantly, a considerable percentage of these cells were able to resume proliferation. Mechanistically, we show that mTORC1 integrates signals from the DNA damage response towards PGC-1β-dependent mitochondrial biogenesis, playing a causal role in the development of senescence. Secondly we show that inhibition of IL-8, a prominent proinflammatory cytokine of the SASP, partially abrogated the senescent phenotype by reducing mTOR-dependent mitochondrial mass and ROS production during senescence. Finally, we demonstrate that inhibition of mitochondrial content in vivo by either rapamycin or PGC-1β deletion prevents age-dependent increase in senescence in mouse liver. Our results suggest mitochondria as an important target for interventions aiming to reduce the load of senescent cells in ageing tissues.en_US
dc.publisherNewcastle Universityen_US
dc.titleInteractions between mitochondria and inflammatory factors during cellular senescenceen_US
Appears in Collections:Institute for Ageing and Health

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