Direct control of mitochondrial function by mTOR

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 52; pp. 22229 - 22232
• Main Authors: Ramanathan, Arvind, Schreiber, Stuart L
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.12.2009; National Acad Sciences
• Subjects: 2-deoxyglucose; Amino acids; Aniline Compounds - pharmacology; bcl-X Protein - metabolism; Binding sites; Biological Sciences; Cell growth; Cell lines; cell viability; Cellular metabolism; Endothelial cells; Energy metabolism; Glucose; Glycolysis; Glycolysis - drug effects; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Jurkat Cells; Metabolism; Metabolome; metabolomics; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecules; Oxygen Consumption - drug effects; Protein metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins; Respiration; Sirolimus - pharmacology; Sulfonamides - pharmacology; T lymphocytes; TOR Serine-Threonine Kinases; Voltage-Dependent Anion Channel 1 - metabolism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0912074106

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.