Direct control of mitochondrial function by mTOR.
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Abstract | mTOR is a central regulator of cellular growth and metabolism. Using metabolic profiling and numerous small-molecule probes, we investigated whether mTOR affects immediate control over cellular metabolism by posttranslational mechanisms. Inhibiting the FKBP12/rapamycin-sensitive subset of mTOR functions in leukemic cells enhanced aerobic glycolysis and decreased uncoupled mitochondrial respiration within 25 min. mTOR is in a complex with the mitochondrial outer-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1, is a kinase substrate for mTOR in vitro, and mTOR regulates the association of Bcl-xl with mTOR. Inhibition of mTOR not only enhances aerobic glycolysis, but also induces a state of increased dependence on aerobic glycolysis in leukemic cells, as shown by the synergy between the glycolytic inhibitor 2-deoxyglucose and rapamycin in decreasing cell viability. |
Year of Publication | 2009
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Journal | Proc Natl Acad Sci U S A
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Volume | 106
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Issue | 52
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Pages | 22229-32
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Date Published | 2009 Dec 29
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ISSN | 1091-6490
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DOI | 10.1073/pnas.0912074106
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PubMed ID | 20080789
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PubMed Central ID | PMC2796909
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Grant list | R01 GM038627 / GM / NIGMS NIH HHS / United States
R37 GM038627 / GM / NIGMS NIH HHS / United States
GM38627 / GM / NIGMS NIH HHS / United States
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