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Aging
10 22, 2016;8 (10): 2551-2567.

Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria.

Satomi Miwa, Rafal Czapiewski, Tengfei Wan, Amy Bell, Kirsten N Hill, Thomas von Zglinicki, Gabriele Saretzki
Author Information
  1. Satomi Miwa: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
  2. Rafal Czapiewski: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
  3. Tengfei Wan: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
  4. Amy Bell: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
  5. Kirsten N Hill: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
  6. Thomas von Zglinicki: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
  7. Gabriele Saretzki: Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
PMID: 27777385 DOI: 10.18632/aging.101089

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.

Keywords

aging brain dietary restriction rapamycin telomerase

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Grants

  1. BB/F010966/1/Biotechnology and Biological Sciences Research Council
  2. BB/I020748/1/Biotechnology and Biological Sciences Research Council
  3. BB/K019260/1/Biotechnology and Biological Sciences Research Council

MeSH Term

Aniline Compounds
Animals
Brain
Mice
Mice, Knockout
Mitochondria
Nitriles
Oxidative Stress
Quinolines
Reactive Oxygen Species
Signal Transduction
Sirolimus
TOR Serine-Threonine Kinases
Telomerase
src-Family Kinases

Chemicals

Aniline Compounds
Nitriles
Quinolines
Reactive Oxygen Species
bosutinib
mTOR protein, mouse
src-Family Kinases
TOR Serine-Threonine Kinases
Telomerase
Tert protein, mouse
Sirolimus
Journal Article

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