Direct control of mitochondrial function by mTOR.

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.
Mesh Terms:
Aniline Compounds, Glycolysis, Humans, In Vitro Techniques, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Metabolome, Mitochondria, Oxygen Consumption, Protein-Serine-Threonine Kinases, Sirolimus, Sulfonamides, TOR Serine-Threonine Kinases, Voltage-Dependent Anion Channel 1, bcl-X Protein
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 29, 2009
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