Mitochondria as the Target

Science Signaling  05 Jan 2010:
Vol. 3, Issue 103, pp. ec5
DOI: 10.1126/scisignal.3103ec5

Ramanathan and Schreiber present a mechanism of action for mTOR (mammalian target of rapamycin), a protein kinase that acts in protein complexes to regulate metabolism. A transcriptionally mediated mechanism for control of mitochondrial function has been proposed, but Ramanathan and Schreiber find evidence for a rapid direct effect of mTOR at the membrane of the mitochondria. In human Jurkat cells (a leukemic T cell line), a global screen of intracellular metabolites showed that treatment of cells with rapamycin (to inhibit mTOR function) caused changes indicative of decreased mitochondrial respiration and increased aerobic glycolysis. The metabolic profile of such rapamycin-treated cells was similar to that of cells treated with a pharmacological inhibitor of VDAC2, a mitochondrial membrane protein that mediates substrate transport into mitochondria. Immunoprecipitation experiments showed that mTOR was associated with VDAC1 and with Bcl-xl, a regulatory protein that functions in control of apoptosis and of substrate permeability in the mitochondria. Bcl-xl was phosphorylated in vitro by mTOR, indicating that it might be regulated by mTOR. Treatment of cells with rapamycin caused decreased association of Bcl-xl with mTOR, and a pharmacological inhibitor of the interaction of Bcl-xl (and that of other Bcl proteins) with other proteins also inhibited mitochondrial respiration, whereas overexpression of Bcl-xl made cells less sensitive to mitochondrial effects of rapamycin. The authors, therefore, propose that the mTOR complex may function as a switch at the mitochondrial membrane that regulates the balance between glycolytic and respiratory metabolism. They also note that rapamycin is an effective treatment for certain cancers and better understanding of its effects may help identify susceptible cancers and allow combined therapies that exploit the increased dependence of rapamycin-treated cells on aerobic glycolysis.

A. Ramanathan, S. L. Schreiber, Direct control of mitochondrial function by mTOR. Proc. Natl. Acad. Sci. U.S.A. 106, 22229–22232 (2009). [Abstract] [Full Text]