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

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

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 www.pnas.org/cgi/content/full/0912074106/DCSupplemental.

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

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