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Status |
Public on Dec 01, 2007 |
Title |
mTOR pathway controls mitochondrial gene expression and respiration through the YY1/PGC-1alpha transcriptional complex |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
Mitochondrial oxidative function is tightly controlled to maintain energy homeostasis in response to nutrient and hormonal signals. An important cellular component in the energy sensing response is the target of rapamycin (TOR) kinase pathway; however whether and how mTOR controls mitochondrial oxidative activity is unknown. Here, we show that mTOR kinase activity stimulates mitochondrial gene expression and oxidative function. In skeletal muscle cells and TSC2-/- MEFs, the mTOR inhibitor rapamycin largely decreased gene expression of mitochondrial transcriptional regulators such as PGC-1alpha and the transcription factors ERRalpha and NRFs. As a consequence, mitochondrial gene expression and oxygen consumption were reduced upon mTOR inhibition. Using computational genomics, we identified the transcription factor YY1 as a common target of mTOR and PGC-1alpha that controls mitochondrial gene expression. Inhibition of mTOR resulted in a failure of YY1 to interact and be coactivated by PGC-1alpha. Notably, knock-down of YY1 in skeletal muscle cells caused a significant decrease in mRNAs of mitochondrial regulators and mitochondrial genes that resulted in a decrease in respiration. Moreover, YY1 was required for rapamycin-dependent repression of mitochondrial genes. Thus, we have identified a novel mechanism in which a nutrient sensor (mTOR) balances energy metabolism via transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer. Keywords: comparative genomics, drug treatment response
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Overall design |
Using Affymetrix MOE430 v2 gene chips, biological triplicates of each condition were analyzed: vehicle-treated, rapamycin-treated, gfp-infected, and pgc-1alpha-infected resulting in a total of 12 samples.
Data were analyzed by RMA (with default settings) in BioConductor 1.2 -- one batch for the Rapamycin vs. Vehicle, and another batch for the PGC vs GFP.
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Contributor(s) |
Cunningham JT, Arlow D, Vazquez F, Mootha VK, Puigserver P |
Citation(s) |
18046414 |
Submission date |
Jul 18, 2006 |
Last update date |
Feb 11, 2019 |
Contact name |
Pere Puigserver |
E-mail(s) |
Pere_Puigserver@dfci.harvard.edu
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Phone |
617-582-7977
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Organization name |
Dana-Farber Cancer Institute
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Department |
Cancer Biology
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Lab |
Smith 936
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Street address |
1 Jimmy Fund Way
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City |
Boston |
State/province |
MA |
ZIP/Postal code |
02115 |
Country |
USA |
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Platforms (1) |
GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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Samples (12)
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Relations |
BioProject |
PRJNA96347 |