title: Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria.
abstract: Telomerase in its canonical function maintains telomeres in dividing cells. In addition, the telomerase protein TERT has non-telomeric functions such as shuttling to mitochondria resulting in a decreased oxidative stress, DNA damage and apoptosis. TERT protein persists in adult neurons and can co-localise to mitochondria under various stress conditions. We show here that TERT expression decreased in mouse brain during aging while release of reactive oxygen species (ROS) from the mitochondrial electron transport chain increased. Dietary restriction (DR) caused accumulation of TERT protein in mouse brain mitochondria correlating to decreased ROS release and improved learning and spatial short-term memory. Decreased mTOR signalling is a mediator of DR. Accordingly, feeding mice with rapamycin increased brain mitochondrial TERT and reduced ROS release. Importantly, the beneficial effects of rapamycin on mitochondrial function were absent in brains and fibroblasts from first generation TERT -/- mice, and when TERT shuttling was inhibited by the Src kinase inhibitor bosutinib. Taken together, our data suggests that the mTOR signalling pathway impinges on the mitochondrial localisation of TERT protein, which might in turn contribute to the protection of the brain by DR or rapamycin against age-associated mitochondrial ROS increase and cognitive decline.
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Satomi
authors: S
authors: Miwa
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Rafal
authors: R
authors: Czapiewski
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Tengfei
authors: T
authors: Wan
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Amy
authors: A
authors: Bell
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Kirsten N
authors: KN
authors: Hill
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Thomas
authors: T
authors: von Zglinicki
authors: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors: Gabriele
authors: G
authors: Saretzki
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D011804:Quinolines; D017382:Reactive Oxygen Species; C471992:bosutinib; C546843:mTOR protein, mouse; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase; C509187:Tert protein, mouse; D020123:Sirolimus
keywords: aging; brain; dietary restriction; rapamycin; telomerase