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PNAS 106 (52): 22229-22232

Copyright © 2009 by the National Academy of Sciences.


Direct control of mitochondrial function by mTOR

Arvind Ramanathan Stuart L. Schreiber1

Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142

Contributed by Stuart L. Schreiber, October 22, 2009

Received for publication September 28, 2009.

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.

Key Words: metabolomics • mitochondria • chemical biology

Freely available online through the PNAS open access option.

Author contributions: A.R. and S.L.S. designed research; A.R. performed research; A.R. and S.L.S. analyzed data; and A.R. and S.L.S. wrote the paper.

The authors declare no conflicts of interest.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: stuart_schreiber{at}

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