Direct control of mitochondrial function by mTOR.

Proc Natl Acad Sci U S A
Authors
Keywords
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
Journal
Proc Natl Acad Sci U S A
Volume
106
Issue
52
Pages
22229-32
Date Published
2009 Dec 29
ISSN
1091-6490
DOI
10.1073/pnas.0912074106
PubMed ID
20080789
PubMed Central ID
PMC2796909
Links
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