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Mechanism and Function of mTOR Targeting to Mitochondria

by
Ming-Feng Lin
M.S., National Yang-Ming University - 2001


Thesis Advisor: X.F. Steven Zheng, Ph.D.
Graduate Program in Molecular & Cellular Pharmacology


Pharmacology Department Conference Room
4th floor, RWJMS Research Tower
Piscataway

Thursday, June 9, 2011
1:00 p.m.


Abstract

As a nutrient sensor and a major growth regulator, mTORC1 pathway is frequently associated with oncogenesis and is a key anticancer drug target. mTOR is present in several organelles, including ER, Golgi, lysosome and mitochondria; however, the mechanisms and the physiological significance of mTOR intracellular localization remain poorly understood. Here we show that mTORC1 distribution within the cytoplasm is regulated by serum and nutrients. Starvation causes mTORC1 to relocate to mitochondria from perinuclear region ER/Golgi, and vice verse, which correlates with mTORC1 activity. These observations suggest that differential mTOR localization plays a role in mTOR signaling.
To characterize the molecular basis of mTOR localization, we found that mTOR mitochondrial localization is mediated by three novel mitochondrial localization sequences (MLSs). Point mutations in MLS motifs disrupt mTOR mitochondrial localization and render resistance of mTORC1 signaling to starvation conditions. In contrast, targeting mTORC1 to mitochondrial by fusion TOM20 mitochondrial targeting sequence with Raptor inhibits mTORC1 signaling. The FKBP38, an integral mitochondrial membrane protein, and the small GTPase Rheb play crucial roles in controlling the proper localization of mTOR. Altogether, these observations reveal a novel mechanism for spatial regulation of mTORC1 activity, which has implications in developing new anti-cancer therapy.


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