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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts
Aging cell, v 12(6), pp 966-977
01 Dec 2013
PMID: 23795962
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts
- Creators
- Chad Lerner - Drexel UniversityAlessandro Bitto - Drexel UniversityDaniel Pulliam - Department of Cellular and Structural Biology Barshop Institute for Longevity and Aging Studies University of Texas Health Sciences Center San Antonio TX 78245 USATimothy Nacarelli - Drexel UniversityMina Konigsberg - Universidad Autónoma MetropolitanaHolly Van Remmen - Department of Cellular and Structural Biology Barshop Institute for Longevity and Aging Studies University of Texas Health Sciences Center San Antonio TX 78245 USAClaudio Torres - Drexel UniversityChristian Sell - Drexel University
- Publication Details
- Aging cell, v 12(6), pp 966-977
- Publisher
- Wiley
- Number of pages
- 12
- Grant note
- Fulbright Scholarship CONACYT; Consejo Nacional de Ciencia y Tecnologia (CONACyT) R01AG022334 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Drexel Aging Initiative
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Neurobiology and Anatomy
- Web of Science ID
- WOS:000327211700004
- Scopus ID
- 2-s2.0-84888135529
- Other Identifier
- 991019168148404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Geriatrics & Gerontology