These authors contributed equally to this work.
Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts
Article first published online: 30 JUL 2013
© 2013 the Anatomical Society and John Wiley & Sons Ltd
Volume 12, Issue 6, pages 966–977, December 2013
How to Cite
Lerner, C., Bitto, A., Pulliam, D., Nacarelli, T., Konigsberg, M., Van Remmen, H., Torres, C. and Sell, C. (2013), Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts. Aging Cell, 12: 966–977. doi: 10.1111/acel.12122
- Issue published online: 21 NOV 2013
- Article first published online: 30 JUL 2013
- Accepted manuscript online: 24 JUN 2013 06:49AM EST
- Manuscript Accepted: 9 JUN 2013
- CONACYT. Grant Number: AG022334
- Drexel Aging Initiative
- mammalian target of rapamycin;
Coordinated expression of mitochondrial and nuclear genes is required to maintain proper mitochondrial function. However, the precise mechanisms that ensure this coordination are not well defined. We find that signaling from mitochondria to the nucleus is influenced by mammalian target of rapamycin (mTOR) activity via changes in autophagy and p62/SQSTM1 turnover. Reducing mTOR activity increases autophagic flux, enhances mitochondrial membrane potential, reduces reactive oxygen species within the cell, and increases replicative life span. These effects appear to be mediated in part by an interaction between p62/SQSTM1 and Keap1. This interaction allows nuclear accumulation of the nuclear factor erythroid 2-like 2 (NFE2L2, also known as nuclear factor related factor 2 or NRF2), increased expression of the nuclear respiratory factor 1 (NRF1), and increased expression of nuclear-encoded mitochondrial genes, such as the mitochondrial transcription factor A, and mitochondrial-encoded genes involved in oxidative phosphorylation. These findings reveal a portion of the intracellular signaling network that couples mitochondrial turnover with mitochondrial renewal to maintain homeostasis within the cell and suggest mechanisms whereby a reduction in mTOR activity may enhance longevity.